Psychostimulants have both acute and long-lasting effects on behavior. In humans, they acutely increase alertness and produce a sense of well-being. In animal studies, low doses of psychostimulants reduce the time spent sleeping or quiescent, while causing increased locomotor activity. Psychostimulants also tend to increase the rate at which previously learned actions are performed, such as pressing a bar for a reward (Lyon and Robbins 1975xThe action of central nervous system drugs (a general theory concerning amphetamine effects) . Lyon, M. and Robbins, T. Curr. Dev. Psychopharmacol. 1975; 2: 80–163

See all ReferencesLyon and Robbins 1975). As the dose increases, the range of observed behavior decreases, until at high doses “stereotypies” are observed—perseverative repetitions of a motor activity, such as sniffing or biting (Randrup and Munkvad 1967xStereotyped activities produced by amphetamine in several animal species and man. Randrup, A. and Munkvad, I. Psychopharmacologia. 1967; 11: 300–310

Crossref | PubMed | Scopus (111)See all ReferencesRandrup and Munkvad 1967). If cocaine or amphetamine is used repeatedly, some acute drug effects may diminish (“tolerance”), while others are enhanced (“sensitization”). Whether tolerance or sensitization occurs depends in part on the pattern of drug administration. Animals given several drug injections spaced out at intervals of a day or more tend to show sensitized locomotor activity and stereotypy, progressively increasing with each injection. Animals given the drug continuously through an osmotic pump, or by closely spaced injections, show a diminished locomotor response to a subsequent challenge dose (192xIntermittent versus continuous stimulation (effect of time interval on the development of sensitization or tolerance) . Post, R.M. Life Sci. 1980; 26: 1275–1282

Crossref | PubMed | Scopus (150)See all References, 136xEffects of interdose interval on ambulatory sensitization to methamphetamine, cocaine and morphine in mice. Kuribara, H. Eur. J. Pharmacol. 1996; 316: 1–5

Crossref | PubMed | Scopus (34)See all References).

Neural changes responsible for tolerance and sensitization can coexist. For example, Dalia et al. 1998xTransient amelioration of the sensitization of cocaine-induced behaviors in rats by the induction of tolerance. Dalia, A.D., Norman, M.K., Tabet, M.R., Schlueter, K.T., Tsibulsky, V.L., and Norman, A.B. Brain Res. 1998; 797: 29–34

Crossref | PubMed | Scopus (9)See all ReferencesDalia et al. 1998 gave intermittent injections of cocaine (40 mg/kg, given at 3-day intervals) and observed a sensitized response to a challenge dose of cocaine (7.5 mg/kg). They then implanted the same animals with an osmotic pump that delivered cocaine continuously (80 mg/kg/day) for 7 days. One day after the pump was removed, the animals displayed tolerance to the challenge dose. However, by 10 days after pump removal, they once again displayed a sensitized response to the challenge. Thus, neural mechanisms of tolerance can mask the expression of sensitization, but may fade more rapidly (e.g., Kalivas and Duffy 1993xTime course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. Kalivas, P.W. and Duffy, P. J. Neurosci. 1993; 13: 266–275

PubMedSee all ReferencesKalivas and Duffy 1993). Sensitized locomotor activity can persist in rats for over a year after the end of drug administration (Paulson et al. 1991xTime course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Paulson, P.E., Camp, D.M., and Robinson, T.E. Psychopharmacology (Berl.). 1991; 103: 480–492

Crossref | PubMedSee all ReferencesPaulson et al. 1991).

A drug user who abruptly stops active drug use may display withdrawal symptoms. Some drugs give rise to clear “physical” symptoms of withdrawal, such as hypertension or abdominal cramps after stopping opiate use, or seizures after ceasing heavy alcohol use (Goldstein 1994xGoldstein, A.

See all ReferencesGoldstein 1994). All addictive drugs, including psychostimulants, can produce emotional withdrawal symptoms such as dysphoria and anhedonia, a diminished capacity for experiencing pleasure (e.g., 75xCocaine dependence. Gawin, F.H. and Ellinwood, E.H. Jr. Annu. Rev. Med. 1989; 40: 149–161

Crossref | PubMedSee all References, 149xPostcocaine anhedonia. An animal model of cocaine withdrawal. Markou, A. and Koob, G.F. Neuropsychopharmacology. 1991; 4: 17–26

PubMedSee all References), although such symptoms are not always observed, even in individuals who use drugs compulsively. The behavioral phenomena of tolerance and withdrawal symptoms both appear to result, at least in part, from compensatory adaptations that occur during drug administration. In response to potent stimulation by drugs, such adaptations act to maintain equilibrium by reducing drug effects (tolerance). In the absence of the drug, these adaptations are unmasked, and a subset of these may produce symptoms generally opposite to those of the drug (withdrawal). A role for such neuroadaptations has been most convincingly documented for the opiate physical withdrawal syndrome (Nestler and Aghajanian 1997xMolecular and cellular basis of addiction. Nestler, E.J. and Aghajanian, G.K. Science. 1997; 278: 58–63

Crossref | PubMed | Scopus (909)See all ReferencesNestler and Aghajanian 1997). It should be noted, however, that for some forms of tolerance, e.g., in opiate analgesia, there is increasing evidence for involvement of associative learning mechanisms (Cepeda-Benito et al. 1999xContext-specific morphine tolerance on the paw-pressure and tail-shock vocalization tests (evidence of associative tolerance without conditioned compensatory responding) . Cepeda-Benito, A., Tiffany, S.T., and Cox, L.S. Psychopharmacology (Berl.). 1999; 145: 426–432

Crossref | PubMed | Scopus (10)See all ReferencesCepeda-Benito et al. 1999).

Tolerance and withdrawal are the defining aspects of drug “dependence.” In contrast, human addiction is defined by uncontrolled, compulsive drug use despite negative consequences. Dependence narrowly defined can occur without addiction (for example, in patients requiring morphine for cancer pain, or benzodiazepines for panic disorder; 186xThe benzodiazepine withdrawal syndrome. Petursson, H. Addiction. 1994; 89: 1455–1459

Crossref | PubMed | Scopus (69)See all References, 261xBenzodiazepine side effects (role of pharmacokinetics and pharmacodynamics) . Vgontzas, A.N., Kales, A., and Bixler, E.O. Pharmacology. 1995; 51: 205–223

Crossref | PubMedSee all References). In addition to being insufficient for addiction, dependence is also not necessary. Both withdrawal symptoms and drug tolerance tend to disappear within a few days or weeks (74xCocaine addiction (psychology and neurophysiology) . Gawin, F.H. Science. 1991; 251: 1580–1586

Crossref | PubMedSee all References, 183xTime course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Paulson, P.E., Camp, D.M., and Robinson, T.E. Psychopharmacology (Berl.). 1991; 103: 480–492

Crossref | PubMedSee all References) and are therefore unlikely to account for the persistence of drug addiction. As has been pointed out before, it is therefore essential to distinguish between neural alterations that account for dependence and those that responsible for compulsive drug use (Wise and Bozarth 1987xA psychomotor stimulant theory of addiction. Wise, R.A. and Bozarth, M.A. Psychol. Rev. 1987; 94: 469–492

Crossref | PubMedSee all ReferencesWise and Bozarth 1987) and late relapse.

Humans and other animals can readily learn to take addictive drugs; this process requires the specific recognition of drug-associated cues and the performance of specific, often complex, actions. Self-administration of psychostimulants may involve several distinct forms of learning (197xLimbic-striatal interactions in reward-related processes. Robbins, T.W., Cador, M., Taylor, J.R., and Everitt, B.J. Neurosci, Biobehav. Rev. 1989; 13: 155–162

Crossref | PubMedSee all References, 267xReward or reinforcement (what's the difference?) . White, N.M. Neurosci. Biobehav. Rev. 1989; 13: 181–186

Crossref | PubMedSee all References, 268xAddictive drugs as reinforcers (multiple partial actions on memory systems) . White, N.M. Addiction. 1996; 91: 921–965

Crossref | PubMed | Scopus (221)See all References). An action that is followed by administration of psychostimulants, such as pressing a lever for intravenous injection, tends to be repeated (“reinforced”; e.g., Woolverton 1992xCocaine self-administration (pharmacology and behavior) . Woolverton, W.L. NIDA Res. Monogr. 1992; 124: 189–202

PubMedSee all ReferencesWoolverton 1992). In addition, cues associated with drug administration acquire motivational significance; for example, rats will choose to spend more time in a location in which they have passively received an injection of psychostimulants than in another location paired with saline injection (“conditioned place preference”; Tzschentke 1998xMeasuring reward with the conditioned place preference paradigm (a comprehensive review of drug effects, recent progress and new issues) . Tzschentke, T.M. Prog. Neurobiol. 1998; 56: 613–672

Crossref | PubMed | Scopus (716)See all ReferencesTzschentke 1998). Psychostimulants act to enhance memory consolidation in general, even facilitating learning of specific behaviors unrelated to drug intake. For example, systemic injections of amphetamine after training can enhance learning of discrimination or avoidance tasks (133xFacilitating effects of pre- and posttrial amphetamine administration on discrimination learning in mice. Krivanek, J.A. and McGaugh, J.L. Agents Actions. 1969; 1: 36–42

Crossref | PubMed | Scopus (33)See all References, 266xEffect of nigrostriatal dopamine depletion on the post-training, memory-improving action of amphetamine. White, N.M. Life Sci. 1988; 43: 7–12

Crossref | PubMedSee all References, and references therein).

There is evidence that relapses among drug-addicted humans also involve associative learning. Relapse often occurs when addicts encounter people, places, or other cues associated with their prior drug use (e.g., 42xRole of conditioning factors in the development of drug dependence. Childress, A.R., McLellan, A.T., and O'Brien, C.P. Psychiatr. Clin. North Am. 1986; 9: 413–425

PubMedSee all References, 235xFirst lapses to smoking (within-subjects analysis of real-time reports) . Shiffman, S., Paty, J.A., Gnys, M., Kassel, J.A., and Hickcox, M. J. Consult. Clin. Psychol. 1996; 64: 366–379

Crossref | PubMed | Scopus (393)See all References). In contrast, the great majority of US soldiers who became addicted to heroin in Vietnam were able to stop drug use upon returning to the distinct context of the United States (Robins et al. 1975xNarcotic use in southeast Asia and afterward. An interview study of 898 Vietnam returnees. Robins, L.N., Helzer, J.E., and Davis, D.H. Arch. Gen. Psychol. 1975; 32: 955–961

Crossref | PubMedSee all ReferencesRobins et al. 1975). In laboratory studies, drug users display conditioned emotional responses to drug-associated cues, including increased expressed desire for drugs (e.g., Ehrman et al. 1992xConditioned responses to cocaine-related stimuli in cocaine abuse patients. Ehrman, R.N., Robbins, S.J., Childress, A.R., and O'Brien, C.P. Psychopharmacology (Berl.). 1992; 107: 523–529

Crossref | PubMed | Scopus (279)See all ReferencesEhrman et al. 1992). Conditioned responses to drug-associated cues persist far longer than withdrawal symptoms (O'Brien et al. 1992xClassical conditioning in drug-dependent humans. O'Brien, C.P., Childress, A.R., McLellan, A.T., and Ehrman, R. Ann. NY Acad. Sci. 1992; 654: 400–415

Crossref | PubMedSee all ReferencesO'Brien et al. 1992) and can occur despite years of abstinence from drugs.

As behavioral sensitization to drugs can also be persistent, it has been considered a model for some aspects of addiction. Sensitization can be operationally defined as a leftward shift in the drug's dose–response curve (Altman et al. 1996xThe biological, social and clinical bases of drug addiction (commentary and debate) . Altman, J., Everitt, B.J., Glautier, S., Markou, A., Nutt, D., Oretti, R., Phillips, G.D., and Robbins, T.W. Psychopharmacology (Berl.). 1996; 125: 285–345

Crossref | PubMed | Scopus (194)See all ReferencesAltman et al. 1996). Mechanistically, this could arise in at least two different ways. The drug could have an increased pharmacological effect, for example as a result of increasing the number of drug receptors or strengthening their coupling to effector proteins. Alternatively, an increased behavioral effect could result from the drug acting on neural circuits in which there are altered patterns of stored information, resulting from prior associative learning. While both forms of sensitization probably occur under certain circumstances, many experiments have demonstrated a role for associative learning in psychostimulant sensitization. If, for example, a rat is taken from its home cage to a novel “test” cage for intermittent amphetamine injections, the sensitized locomotor response to a challenge dose is much greater if the challenge is also given in that test cage than if given in a different environment (e.g., 95xSensitization to the behavioral effects of cocaine (modification by Pavlovian conditioning) . Hinson, R.E. and Poulos, C.X. Pharmacol. Biochem. Behav. 1981; 15: 559–562

Crossref | PubMedSee all References, 7xThe development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment. Badiani, A., Anagnostaras, S.G., and Robinson, T.E. Psychopharmacology (Berl.). 1995; 117: 443–452

Crossref | PubMed | Scopus (121)See all References). Several groups have demonstrated that this “context dependence” can be complete—i.e., substantial sensitization expressed in the drug-associated location, no sensitization at all in a different environment (for reviews, see 185xConditioning as a critical determinant of sensitization induced by psychomotor stimulants. Pert, A., Post, R., and Weiss, S.R. NIDA Res. Monogr. 1990; 97: 208–241

PubMedSee all References, 5xSensitization to the psychomotor stimulant effects of amphetamine (modulation by associative learning) . Anagnostaras, S.G. and Robinson, T.E. Behav. Neurosci. 1996; 110: 1397–1414

Crossref | PubMed | Scopus (199)See all References; for recent examples, see Tirelli and Terry 1998xAmphetamine-induced conditioned activity and sensitization (the role of habituation to the test context and the involvement of Pavlovian processes) . Tirelli, E. and Terry, P. Behav. Pharmacol. 1998; 9: 409–419

Crossref | PubMedSee all ReferencesTirelli and Terry 1998). Even without an acute drug injection, an animal placed back in the drug-associated environment will often show a conditioned response, repeating in part the behavior previously performed there (such as locomotor activity or stereotypy). Discrete stimuli such as tones or lights that are paired with drug administration can also come to control both sensitization and conditioned locomotion (189xConditioning of the activity effects of drugs. Pickens, R. and Dougherty, J.A. : 39–50

CrossrefSee all References, 23xClassical conditioning of cocaine's stimulatory effects. Bridger, W.H., Schiff, S.R., Cooper, S.S., Paredes, W., and Barr, G.A. Psychopharmacol. Bull. 1982; 18: 210–214

PubMedSee all References, 180xConditioned locomotor-activating and reinforcing effects of discrete stimuli paired with intraperitoneal cocaine. Panlilio, L.V. and Schindler, C.W. Behav. Pharmacol. 1997; 8: 691–698

Crossref | PubMed | Scopus (26)See all References). At least some aspects of sensitization also involve performance of learned responses to specific stimuli and contexts, rather than enhancement of an unlearned locomotor response to drug. A sensitized stereotypy response to amphetamine appears to consist largely of behavioral elements performed during the prior exposure to drug (Ellinwood and Kilbey 1975xAmphetamine stereotypy (the influence of environmental factors and prepotent behavioral patterns on its topography and development) . Ellinwood, E.H. Jr. and Kilbey, M.M. Biol. Psychiatry. 1975; 10: 3–16

PubMedSee all ReferencesEllinwood and Kilbey 1975), and the expression of this response is diminished in a novel environment (Robbins et al. 1990xThe neuropsychological significance of stereotypy induced by stimulant drugs. Robbins, T.W., Mittleman, G., O'Brien, J., and Winn, P.

See all ReferencesRobbins et al. 1990). Also, mice prevented from moving around freely during initial exposure to psychostimulants do not exhibit locomotor sensitization to a subsequent dose (137xInhibitory effect of restraint on induction of behavioral sensitization to methamphetamine and cocaine in mice. Kuribara, H. Pharmacol. Biochem. Behav. 1996; 54: 327–331

Crossref | PubMed | Scopus (9)See all References, 138xEffects of postmethamphetamine treatment with restraint on ambulatory sensitization to methamphetamine in mice. Kuribara, H. Brain Res. Bull. 1997; 43: 97–100

Crossref | PubMed | Scopus (8)See all References).

Context-dependent sensitization and cue-conditioned human relapse suggest that the brain stores specific patterns of drug-related information. In contrast, other mechanisms appear to regulate the overall responsiveness of an organism. Such mechanisms can produce either context-independent sensitization (see below; Stewart 1992xNeurobiology of conditioning to drugs of abuse. Stewart, J. Ann. NY Acad. Sci. 1992; 654: 335–346

Crossref | PubMedSee all ReferencesStewart 1992) or, as in the state of psychostimulant withdrawal, a general reduction in responsiveness to a broad range of information, resembling mild depression (Gawin and Ellinwood 1989xCocaine dependence. Gawin, F.H. and Ellinwood, E.H. Jr. Annu. Rev. Med. 1989; 40: 149–161

Crossref | PubMedSee all ReferencesGawin and Ellinwood 1989). In the remainder of this review, we examine neurobiological evidence supporting this distinction (see Table 1Table 1), and consider how neural mechanisms involved in normal memory formation might also be responsible for compulsive drug use.

Psychostimulants act at axonal terminals of neurons that release monoamines (dopamine, serotonin, and norepinephrine). Psychostimulants increase the extracellular concentrations of these neuromodulators: cocaine by blocking transporter-mediated reuptake and amphetamine by promoting efflux from synaptic terminals (for review, see Seiden, 1993). Many brain regions receive monoamine inputs, including striatum, neocortex, amygdala, and hippocampus (Fallon and Loughlin 1995xSubstantia nigra. Fallon, J.H. and Loughlin, S.E.

See all ReferencesFallon and Loughlin 1995), and following psychostimulant administration, markers of brain activity are altered in many structures (e.g., 244xCocaine's time action profile on regional cerebral blood flow in the rat. Stein, E.A. and Fuller, S.A. Brain Res. 1993; 626: 117–126

Crossref | PubMedSee all References, 145xCocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. Lyons, D., Friedman, D.P., Nader, M.A., and Porrino, L.J. J. Neurosci. 1996; 16: 1230–1238

PubMedSee all References, 22xAcute effects of cocaine on human brain activity and emotion. Breiter, H.C., Gollub, R.L., Weisskoff, R.M., Kennedy, D.N., Makris, N., Berke, J.D., Goodman, J.M., Kantor, H.L., Gastfriend, D.R., Riorden, J.P. et al. Neuron. 1997; 19: 591–611

Abstract | Full Text | Full Text PDF | PubMed | Scopus (742)See all References). While the full diversity of drug effects is mediated by multiple neurotransmitters acting in multiple brain regions, most addictive drugs share the common property of increasing dopamine release in the striatum (e.g., 54xDrugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Di Chiara, G. and Imperato, A. Proc. Natl. Acad. Sci. USA. 1988; 85: 5274–5278

Crossref | PubMedSee all References, 134xAmphetamine, cocaine, and fencamfamine (relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics) . Kuczenski, R., Segal, D.S., and Aizenstein, M.L. J. Neurosci. 1991; 11: 2703–2712

PubMedSee all References). The dopamine input to the striatum is provided by a very dense network of axon terminals arising from cell bodies in the midbrain–substantia nigra pars compacta and ventral tegmental area (see Fallon and Loughlin 1995xSubstantia nigra. Fallon, J.H. and Loughlin, S.E.

See all ReferencesFallon and Loughlin 1995). The increased locomotor activity and stereotypy caused by psychostimulants seem especially to involve dopamine release in ventral and dorsal parts of striatum, respectively (Kelly et al. 1975xAmphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Kelly, P.H., Seviour, P.W., and Iversen, S.D. Brain Res. 1975; 94: 507–522

Crossref | PubMed | Scopus (480)See all ReferencesKelly et al. 1975). The ventral striatum includes the “core” and “shell” of the nucleus accumbens (see Heimer et al. 1991xSpecificity in the projection patterns of accumbal core and shell in the rat. Heimer, L., Zahm, D.S., Churchill, L., Kalivas, P.W., and Wohltmann, C. Neuroscience. 1991; 41: 89–125

Crossref | PubMed | Scopus (634)See all ReferencesHeimer et al. 1991); blockade of dopamine neurotransmission in this region attenuates most rewarding effects of addictive drugs, such as conditioned place preference (see Wise 1996xAddictive drugs and brain stimulation reward. Wise, R.A. Annu. Rev. Neurosci. 1996; 19: 319–340

Crossref | PubMedSee all ReferencesWise 1996 and references therein). The dopaminergic projection to ventral striatum has therefore been intensely investigated for its potential involvement in addiction (for review, see Self and Nestler 1995xMolecular mechanisms of drug reinforcement and addiction. Self, D.W. and Nestler, E.J. Annu. Rev. Neurosci. 1995; 18: 463–495

Crossref | PubMedSee all ReferencesSelf and Nestler 1995).

The dorsal and ventral striatum are components of large-scale neural circuits, encompassing the cerebral cortex, basal ganglia, and thalamus (Figure 1Figure 1; for reviews, see 3xBasal ganglia-thalamocortical circuits (parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions) . Alexander, G.E., Crutcher, M.D., and DeLong, M.R. Prog. Brain Res. 1990; 85: 119–146

Crossref | PubMedSee all References, 76xThe basal ganglia. Gerfen, C.R. and Wilson, C.J.

See all References). The striatum receives glutamatergic inputs from all cortical areas. Neocortical areas project mainly to more dorsal parts of striatum, while other regions such as hippocampus and amygdala project mainly to ventral parts of striatum (e.g., McGeorge and Faull 1989xThe organization of the projection from the cerebral cortex to the striatum in the rat. McGeorge, A.J. and Faull, R.L. Neuroscience. 1989; 29: 503–537

Crossref | PubMedSee all ReferencesMcGeorge and Faull 1989). Ninety to ninety-five percent of striatal neurons are medium-sized GABAergic cells, with dendrites that have a dense population of spines. These spines receive synaptic contacts from glutamatergic afferents; each spiny cell receives synapses from thousands of distinct cortical neurons (Kincaid et al. 1998xConnectivity and convergence of single corticostriatal axons. Kincaid, A.E., Zheng, T., and Wilson, C.J. J. Neurosci. 1998; 18: 4722–4731

PubMedSee all ReferencesKincaid et al. 1998). This anatomical organization is consistent with the idea that spiny cells integrate information from many sources and contrasts with the point-to-point transmission of information that characterizes, for example, primary sensory cortical areas. Medium spiny neurons are silent most of the time, until simultaneous activity in many glutamatergic afferents pushes them into an active mode (the “up” state); once in this mode, small changes in input can then trigger action potentials, and the cells fire in bursts (Stern et al. 1998xMembrane potential synchrony of simultaneously recorded striatal spiny neurons in vivo. Stern, E.A., Jaeger, D., and Wilson, C.J. Nature. 1998; 394: 475–478

Crossref | PubMed | Scopus (178)See all ReferencesStern et al. 1998). This activity of striatal neurons is frequently observed to be context dependent. A striatal neuron, for example, may fire in conjunction with a particular movement made as part of a specific behavioral task, but not with the same movement in a different behavioral situation (e.g., Kimura et al. 1992xActivity of primate putamen neurons is selective to the mode of voluntary movement (visually guided, self-initiated or memory-guided) . Kimura, M., Aosaki, T., Hu, Y., Ishida, A., and Watanabe, K. Exp. Brain Res. 1992; 89: 473–477

Crossref | PubMedSee all ReferencesKimura et al. 1992).

Figure 1

Simplified Anatomy of Cortex–Basal Ganglia Circuits

Multiple circuits project from a wide range of cortical regions through the basal ganglia and back to cortex. The processing of discrete patterns of information in these circuits can be modulated by the diffuse dopamine input from the midbrain. D1-type dopamine receptors are located pricipally on striatal neurons projecting to GPi/SNr, while D2-type dopamine receptors are principally on striatal neurons projecting to GPe. Additional important connections, such as the direct cortical projection to STN and dopamine inputs to other forebrain areas, are omitted for simplicity. Abbreviations: GPe, globus pallidus–external; GPi, globus pallidus–internal; STN, subthalamic nucleus; SNr, substantia nigra pars reticulata; SNc/VTA, substantia nigra pars compacta/ventral tegmental area; THAL, thalamus; HIPP, hippocampus; AMYG, amygdala.

View Large Image | View Hi-Res Image | Download PowerPoint Slide

Striatal spiny neurons themselves project out of the striatum; half of these projections form the “direct” pathway to the internal part of the globus pallidus (GPi; SNr in rodents), while the other half project indirectly to GPi via the external part of the globus pallidus (GPe) and the subthalamic nucleus. From GPi there are projections to the mediodorsal thalamus. This part of the thalamus in turn has (reciprocal) connections with frontal neocortical areas, including prefrontal cortex. Overall, many investigators have suggested that neural circuits through the striatum are involved in response selection and the performance of actions (e.g., 200xThe neuropsychological significance of stereotypy induced by stimulant drugs. Robbins, T.W., Mittleman, G., O'Brien, J., and Winn, P.

See all References, 181xPassingham, R.

See all References, 275xThe frontal cortex-basal ganglia system in primates. Wise, S.P., Murray, E.A., and Gerfen, C.R. Crit. Rev. Neurobiol. 1996; 10: 317–356

Crossref | PubMedSee all References, 25xWhat do the basal ganglia do?. Brown, P. and Marsden, C.D. Lancet. 1998; 351: 1801–1804

Abstract | Full Text | Full Text PDF | PubMed | Scopus (233)See all References).

Superimposed on this cortex–basal ganglia–thalamus–frontal lobe circuitry are the modulatory dopamine projections. The architecture of dopaminergic and other monoaminergic systems in the brain differs markedly from that of neuronal projections involved in communication of detailed information. Dopamine is released by a restricted number of neurons that project widely to a large number of targets. The striatum is so heavily innervated by dopamine terminals that the average distance between release sites is only 4 μm, and the dynamics of dopamine reuptake allow rapid diffusion to nonsynaptic receptors (Gonon 1997xProlonged and extrasynaptic excitatory action of dopamine mediated by D1 receptors in the rat striatum in vivo. Gonon, F. J. Neurosci. 1997; 17: 5972–5978

PubMedSee all ReferencesGonon 1997). Dopamine receptors are commonly found at nonsynaptic sites; they do not seem to be clustered at synapses (Caille et al. 1996xUltrastructural localization of D1 dopamine receptor immunoreactivity in rat striatonigral neurons and its relation with dopaminergic innervation. Caille, I., Dumartin, B., and Bloch, B. Brain Res. 1996; 730: 17–31

Crossref | PubMedSee all ReferencesCaille et al. 1996). In addition, they are G protein coupled; Hille has pointed out that the characteristics of G protein signaling, such as high affinity for agonists and spare receptors, encourage extrasynaptic transmission (Hille 1992xG protein–coupled mechanisms and nervous signaling. Hille, B. Neuron. 1992; 9: 187–195

Abstract | Full Text PDF | PubMed | Scopus (241)See all ReferencesHille 1992). When dopaminergic axons or cell bodies are briefly stimulated with a burst of current pulses, the resulting increase in striatal dopamine is transient, lasting less than a second (83xProlonged and extrasynaptic excitatory action of dopamine mediated by D1 receptors in the rat striatum in vivo. Gonon, F. J. Neurosci. 1997; 17: 5972–5978

PubMedSee all References, 73xDissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation. Garris, P.A., Kilpatrick, M., Bunin, M.A., Michael, D., Walker, Q.D., and Wightman, R.M. Nature. 1999; 398: 67–69

Crossref | PubMed | Scopus (199)See all References). Thus, dopamine neurotransmission in striatum may have some temporal specificity (see below), but it is thought that it represents a “global” signal rather than conveying spatially detailed patterns of information (e.g., 221xThe phasic reward signal of primate dopamine neurons. Schultz, W. Adv. Pharmacol. 1998; 42: 686–690

Crossref | PubMed | Scopus (18)See all References, 222xPredictive reward signal of dopamine neurons. Schultz, W. J. Neurophysiol. 1998; 80: 1–27

PubMedSee all References). Neural changes that alter dopamine neurotransmission are therefore unlikely, by themselves, to account for behavioral changes that are specific to particular patterns of information.

Striatal dopamine levels modulate the “behavioral reactivity” of the organism (Salamone 1996xThe behavioral neurochemistry of motivation (methodological and conceptual issues in studies of the dynamic activity of nucleus accumbens dopamine) . Salamone, J.D. J. Neurosci. Methods. 1996; 64: 137–149

Crossref | PubMed | Scopus (122)See all ReferencesSalamone 1996; see also 18xDopamine functions in appetitive and defensive behaviours. Blackburn, J.R., Pfaus, J.G., and Phillips, A.G. Prog. Neurobiol. 1992; 39: 247–279

Crossref | PubMed | Scopus (268)See all References, 201xNeural systems underlying arousal and attention. Implications for drug abuse. Robbins, T.W., Granon, S., Muir, J.L., Durantou, F., Harrison, A., and Everitt, B.J. Ann. NY Acad. Sci. 1998; 846: 222–237

Crossref | PubMed | Scopus (101)See all References). Loss of the dopamine input to striatum results in Parkinson's disease, characterized by slowness in initiating actions. Similarly, mice genetically modified to lack dopamine are hypoactive and stop eating a few weeks after birth; they starve unless given dopaminergic drugs such as L-DOPA, in which case they grow at near normal rates (Zhou and Palmiter 1995xDopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Zhou, Q.Y. and Palmiter, R.D. Cell. 1995; 83: 1197–1209

Abstract | Full Text PDF | PubMed | Scopus (386)See all ReferencesZhou and Palmiter 1995). Adult animals whose dopamine cells are completely destroyed by neurotoxins such as 6-hydroxydopamine (6-OHDA) or MPTP are also akinetic and aphagic (257xAdipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Ungerstedt, U. Acta Physiol. Scand. Suppl. 1971; 367: 95–122

PubMedSee all References, 140xSelective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Langston, J.W., Forno, L.S., Rebert, C.S., and Irwin, I. Brain Res. 1984; 292: 390–394

Crossref | PubMed | Scopus (271)See all References), as are animals given large doses of dopamine-blocking drugs, such as the antipsychotic drug haloperidol. Rats given 6-OHDA lesions or haloperidol may not respond to normal food, but will often eat highly palatable food. Near-normal behavior can also be induced by arousing stimuli such as pinching the tail (227xEffects of mood, motivation, stress and alertness on the performance in Parkinson's disease. Schwab, R.S. and Zieper, I. Psychiatr. Neurol. 1965; 150: 345–357

Crossref | PubMedSee all References, 150xNigrostriatal bundle damage and the lateral hypothalamic syndrome. Marshall, J.F., Richardson, J.S., and Teitelbaum, P. J. Comp. Physiol. Psychol. 1974; 87: 808–830

Crossref | PubMedSee all References, 151xActivation-induced restoration of sensorimotor functions in rats with dopamine-depleting brain lesions. Marshall, J.F., Levitan, D., and Stricker, E.M. J. Comp. Physiol. Psychol. 1976; 90: 536–546

Crossref | PubMedSee all References), and such lesioned animals will swim effectively if placed in a tank of water (Keefe et al. 1989xParadoxical kinesia in parkinsonism is not caused by dopamine release. Studies in an animal model. Keefe, K.A., Salamone, J.D., Zigmond, M.J., and Stricker, E.M. Arch. Neurol. 1989; 46: 1070–1075

Crossref | PubMedSee all ReferencesKeefe et al. 1989). Thus, rather than preventing the capacity for action, removal of dopamine leads to a “psychomotor” deficit, in many ways opposite to the effects of psychostimulants (for review, see Wise and Bozarth 1987xA psychomotor stimulant theory of addiction. Wise, R.A. and Bozarth, M.A. Psychol. Rev. 1987; 94: 469–492

Crossref | PubMedSee all ReferencesWise and Bozarth 1987). Conversely, increases in striatal dopamine levels are observed in response to a wide array of naturally occurring events that are arousing. These include rewarding, novel, and stressful stimuli (for reviews, see 18xDopamine functions in appetitive and defensive behaviours. Blackburn, J.R., Pfaus, J.G., and Phillips, A.G. Prog. Neurobiol. 1992; 39: 247–279

Crossref | PubMed | Scopus (268)See all References, 217xBehavioral functions of nucleus accumbens dopamine (empirical and conceptual problems with the anhedonia hypothesis) . Salamone, J.D., Cousins, M.S., and Snyder, B.J. Neurosci. Biobehav. Rev. 1997; 21: 341–359

Crossref | PubMed | Scopus (329)See all References).

Consistent with the broad set of inputs to striatum, increasing striatal dopamine can enhance behavioral responsiveness to a broad range of information. For example, the ventral striatum receives inputs from nuclei of the amygdala that are thought to process information about the emotional and motivational significance of environmental stimuli (63xThe basolateral amygdala-ventral striatal system and conditioned place preference (further evidence of limbic-striatal interactions underlying reward-related processes) . Everitt, B.J., Morris, K.A., O'Brien, A., and Robbins, T.W. Neuroscience. 1991; 42: 1–18

Crossref | PubMed | Scopus (308)See all References, 156xTopographical organization of amygdaloid projections to the caudatoputamen, nucleus accumbens, and related striatal-like areas of the rat brain. McDonald, A.J. Neuroscience. 1991; 44: 15–33

Crossref | PubMed | Scopus (204)See all References, 88xNeurotoxic lesions of basolateral, but not central, amygdala interfere with Pavlovian second-order conditioning and reinforcer devaluation effects. Hatfield, T., Han, J.S., Conley, M., Gallagher, M., and Holland, P. J. Neurosci. 1996; 16: 5256–5265

PubMedSee all References). Animals will normally work for presentation of a cue that has been previously presented in conjunction with reward. The amount of responding for such “conditioned reinforcers” is increased by injections of amphetamine either systemically or into ventral striatum (27xInvolvement of the amygdala in stimulus-reward associations (interaction with the ventral striatum) . Cador, M., Robbins, T.W., and Everitt, B.J. Neuroscience. 1989; 30: 77–86

Crossref | PubMedSee all References, 116xDopamine and conditioned reinforcement. I. Differential effects of amphetamine microinjections into striatal subregions. Kelley, A.E. and Delfs, J.M. Psychopharmacology (Berl.). 1991; 103: 187–196

Crossref | PubMed | Scopus (83)See all References). Dopamine blockade or destruction of dopamine terminals in ventral striatum block this effect of amphetamine, without preventing responding for “primary” rewards such as food (197xLimbic-striatal interactions in reward-related processes. Robbins, T.W., Cador, M., Taylor, J.R., and Everitt, B.J. Neurosci, Biobehav. Rev. 1989; 13: 155–162

Crossref | PubMedSee all References, 193xDopamine D1 and D2 antagonists attenuate amphetamine-produced enhancement of responding for conditioned reward in rats. Ranaldi, R. and Beninger, R.J. Psychopharmacology (Berl.). 1993; 113: 110–118

Crossref | PubMed | Scopus (23)See all References, 278xRelative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement. Wolterink, G., Phillips, G., Cador, M., Donselaar-Wolterink, I., Robbins, T.W., and Everitt, B.J. Psychopharmacology (Berl.). 1993; 110: 355

Crossref | PubMed | Scopus (109)See all References). Hence, the ventral striatum has been described as an interface between motivational and motor systems in the brain (Mogenson et al. 1980xFrom motivation to action (functional interface between the limbic system and the motor system) . Mogenson, G.J., Jones, D.L., and Yim, C.Y. Prog. Neurobiol. 1980; 14: 69–97

Crossref | PubMedSee all ReferencesMogenson et al. 1980), with dopamine regulating the extent to which previously obtained information about the motivational significance of cues affects ongoing behavior.

In addition to a short-term effect facilitating action, dopamine also regulates learning in striatal circuits. Parkinsonian patients have specific deficits in “habit” or “skill” learning (e.g., 65xBallistic and corrective movements on an aiming task. Intention tremor and parkinsonian movement disorders compared. Flowers, K. Neurology. 1975; 25: 413–421

Crossref | PubMedSee all References, 214xProcedural learning and neostriatal dysfunction in man. Saint-Cyr, J.A., Taylor, A.E., and Lang, A.E. Brain. 1988; 111: 941–959

Crossref | PubMedSee all References, 124xA neostriatal habit learning system in humans. Knowlton, B.J., Mangels, J.A., and Squire, L.R. Science. 1996; 273: 1399–1402

Crossref | PubMedSee all References). This form of associative learning is believed to involve the dorsal striatum, and is characterized by the progressively smoother execution of a particular action or behavioral sequence, generally in response to specific stimuli (for reviews, see 162xMemories and habits (two neural systems) . Mishkin, M., Malamut, B., and Bachevalier, J.

See all References, 269xMnemonic functions of the basal ganglia. White, N.M. Curr. Opin. Neurobiol. 1997; 7: 164–169

Crossref | PubMed | Scopus (135)See all References, 84xThe basal ganglia and chunking of action repertoires. Graybiel, A.M. Neurobiol. Learn. Mem. 1998; 70: 119–136

Crossref | PubMed | Scopus (390)See all References). During the initial learning of a task, one must pay attention, but with many repetitions the process becomes increasingly automatic. This habit learning is a form of “procedural” or “implicit” memory—it is preserved in patients with amnesia who cannot consciously recall the training episodes (Milner et al. 1998xCognitive neuroscience and the study of memory. Milner, B., Squire, L.R., and Kandel, E.R. Neuron. 1998; 20: 445–468

Abstract | Full Text | Full Text PDF | PubMed | Scopus (667)See all ReferencesMilner et al. 1998). Habit learning includes not just overt motor actions but also other tasks involving the gradual, incremental learning of implicit associations (e.g., Knowlton et al. 1996xA neostriatal habit learning system in humans. Knowlton, B.J., Mangels, J.A., and Squire, L.R. Science. 1996; 273: 1399–1402

Crossref | PubMedSee all ReferencesKnowlton et al. 1996). Once established, some learned habits can be hard to extinguish, as they tend to persist even when the outcome becomes less desirable (i.e., they are resistant to devaluation; 4xThe biological, social and clinical bases of drug addiction (commentary and debate) . Altman, J., Everitt, B.J., Glautier, S., Markou, A., Nutt, D., Oretti, R., Phillips, G.D., and Robbins, T.W. Psychopharmacology (Berl.). 1996; 125: 285–345

Crossref | PubMed | Scopus (194)See all References, 11xGoal-directed instrumental action (contingency and incentive learning and their cortical substrates) . Balleine, B.W. and Dickinson, A. Neuropharmacology. 1998; 37: 407–419

Crossref | PubMed | Scopus (436)See all References).

Removal of dopamine interferes with striatally based learning processes; conversely, intrastriatal injections of psychostimulants can enhance learning of striatum-dependent tasks. For example, if rats that are learning to move to a marked target in a water maze are given intrastriatal amphetamine immediately after training, they show enhanced performance the next day (Packard et al. 1994xAmygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes. Packard, M.G., Cahill, L., and McGaugh, J.L. Proc. Natl. Acad. Sci. USA. 1994; 91: 8477–8481

Crossref | PubMedSee all ReferencesPackard et al. 1994). This facilitatory action of psychostimulants on learning appears to respect the topography of cortical afferents to striatum. Amphetamine injections in parts of striatum receiving inputs from visual cortex selectively improve learning of a conditioned response to a visual cue, while injections into regions of striatum receiving inputs from olfactory cortex selectively improve learning of a conditioned response to an olfactory cue (Viaud and White 1989xDissociation of visual and olfactory conditioning in the neostriatum of rats. Viaud, M.D. and White, N.M. Behav. Brain Res. 1989; 32: 31–42

Crossref | PubMedSee all ReferencesViaud and White 1989). Systemic injections of amphetamine can also facilitate learning of such tasks, provided the dopamine input to striatum is intact (White 1988xEffect of nigrostriatal dopamine depletion on the post-training, memory-improving action of amphetamine. White, N.M. Life Sci. 1988; 43: 7–12

Crossref | PubMedSee all ReferencesWhite 1988).

This memory-enhancing effect of striatal dopamine does not require high temporal precision, since it is observed even with psychostimulant injections administered just after the training episodes. However, temporally precise changes in striatal dopamine may play other important roles in learning. Midbrain dopamine cells continuously supply dopamine to the striatum by firing tonically. Schultz and colleagues have found that certain external events, especially unexpected rewards, cause a transient increase in their rate of firing (for review, see Schultz 1998bxPredictive reward signal of dopamine neurons. Schultz, W. J. Neurophysiol. 1998; 80: 1–27

PubMedSee all ReferencesSchultz 1998b). This decrease disappears if the rewarding event comes to be reliably predicted by a prior cue (such as a tone) and instead occurs in response to the predictive cue. Rewards presented without prior cues still elicit an increased response, and if a reward is “expected” from prior cues but omitted, there is a suppression of cell firing at the expected time of reward (Schultz et al. 1993xResponses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. Schultz, W., Apicella, P., and Ljungberg, T. J. Neurosci. 1993; 13: 900–913

PubMedSee all ReferencesSchultz et al. 1993). Recent results using high-speed voltammetry to measure brief changes in dopamine in the rat ventral striatum have also found an important role for prediction (Garris et al. 1999xDissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation. Garris, P.A., Kilpatrick, M., Bunin, M.A., Michael, D., Walker, Q.D., and Wightman, R.M. Nature. 1999; 398: 67–69

Crossref | PubMed | Scopus (199)See all ReferencesGarris et al. 1999). In animals learning to press a lever to cause brief stimulation of dopamine cell bodies (intracranial self-stimulation), the first few lever presses resulted in increased dopamine release, and this dopamine release was necessary for the animals to learn to consistently perform the lever-pressing behavior. However, this dopamine response faded after the first few presses, even though the animals kept pressing the lever to receive stimulation. Unpredictable stimulation of dopamine cell bodies still caused a brief increase in dopamine release. Given these properties, it has been suggested that such transient changes in dopamine release may be evoked when the animal's predictions of rewarding events turn out to be inaccurate and that dopamine is involved in adjusting those predictions (225xReward-related signals carried by dopamine neurons. Schultz, W., Romo, R., Ljungberg, T., Mirenowicz, J., Hollerman, J.R., and Dickinson, A.

See all References, 226xA neural substrate of prediction and reward. Schultz, W., Dayan, P., and Montague, P.R. Science. 1997; 275: 1593–1599

Crossref | PubMed | Scopus (2516)See all References). Transient changes in dopamine levels may correspond to the “error signal” found in certain neural network models of reinforcement learning (12xAdaptive critics and the basal ganglia. Barto, A.G.

See all References, 251xSutton, R.S. and Barto, A.G.

See all References; but see Redgrave et al. 1999xIs the short-latency dopamine response too short to signal reward error?. Redgrave, P., Prescott, T.J., and Gurney, K. Trends Neurosci. 1999; 22: 146–151

Abstract | Full Text | Full Text PDF | PubMed | Scopus (308)See all ReferencesRedgrave et al. 1999).

Dopamine release in striatum can thus both potentiate performance of previously established behaviors (psychostimulation) and assist in the learning of new patterns of behavior (reinforcement/consolidation). We next turn to some of the molecular mechanisms underlying these effects, which are both likely to be important in the long-term effects of addictive drugs.

There are at least five types of dopamine receptors in the vertebrate CNS, and these fall into two classes: D1-type (D1, D5) and D2-type (D2, D3, D4) (for reviews, see 169xMolecular biology of dopamine receptors. Neve, K.A. and Neve, R.L.

CrossrefSee all References, 204xInteractions of dopamine receptors with G-proteins. Robinson, S.W.

See all References). The striatum has a very high density of D1 and D2 dopamine receptors, localized concentrations of D3 receptors in regions of the ventral striatum, and lower levels of D4 and D5 receptors (148xDopamine receptor expression in the central nervous system. Mansour, A. and Watson, S.J.

See all References, 19xInduction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Bordet, R., Ridray, S., Carboni, S., Diaz, J., Sokoloff, P., and Schwartz, J.C. Proc. Natl. Acad. Sci. USA. 1997; 94: 3363–3367

Crossref | PubMed | Scopus (242)See all References). In view of their high striatal density, we focus here on D1 and D2 receptors. D1 receptors are localized primarily on striatal spiny neurons that project to the internal part of the globus pallidus/substantia nigra pars reticulata, while D2 receptors are found on spiny neurons projecting to the external part of the globus pallidus (see Figure 1Figure 1). There are also D2 autoreceptors on the dopaminergic terminals themselves (141xD1 and D2 dopamine receptor gene expression in the rat striatum (sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct neuronal populations of the dorsal and ventral striatum) . Le Moine, C. and Bloch, B. J. Comp. Neurol. 1995; 355: 418–426

Crossref | PubMedSee all References, 120xProminence of the dopamine D2 short isoform in dopaminergic pathways. Khan, Z.U., Mrzljak, L., Gutierrez, A., de la Calle, A., and Goldman-Rakic, P.S. Proc. Natl. Acad. Sci. USA. 1998; 95: 7731–7736

Crossref | PubMed | Scopus (154)See all References). (As shorthand, we shall refer to D1 receptor–bearing striatal medium spiny neurons as “D1 cells” and D2 receptor–bearing striatal spiny neurons as “D2 cells”). D1 receptors are coupled to G_s/G_olf and thus stimulate adenylate cyclase to produce the intracellular second messenger cAMP. cAMP in turn activates cAMP-dependent protein kinase (PKA), which phosphorylates numerous substrates, including L-type calcium channels, transcription factors such as CREB, and other intracellular signaling components (see Figure 2Figure 2). D2 receptors are coupled to G_i/G_o and thus inhibit adenylate cyclase and also activate an inwardly rectifying potassium channel.

Figure 2

Neurotransmitter Control of Striatal IEG Expression

Induction of IEG expression is under the joint control of calcium- and cAMP-dependent signal transduction pathways. In striatum these pathways appear to be mutually inhibitory at many stages (not shown), but their effects inside the nucleus can be cooperative. Both PKA and CaMKIV can phosphorylate CREB at serine 133. Calcium-dependent CREB phosporylation may also occur as a result of activation of the ERK MAPKs in striatal cells. ERK MAPKs also increase transcription of striatal IEGs through phosphorylation of the transcription factor Elk-1. A complex set of genes can be induced in striatal neurons. Some genes appear to be part of a homeostatic response, reducing sensitivity to subsequent stimulation; others may be involved in consolidating changes in the strength of specific synaptic connections. Abbreviations: D1, dopamine D1 receptor; D2, dopamine D2 receptor; PKA, cAMP-dependent protein kinase; CaM, calmodulin; CaMKIV, calcium/calmodulin-dependent protein kinase IV; MEK, MAP and ERK kinase; MAPK, mitogen-activated protein kinase; SRF, serum response factor; AP-1, activator protein-1; CRE, cAMP response element; CREB, CRE binding protein; TBP, TATA binding protein; RNA pol II, RNA polymerase II.

View Large Image | View Hi-Res Image | Download PowerPoint Slide

Striatal D2 receptors are tonically (continuously) stimulated by basal levels of dopamine, and this tonic activity is important for normal motor behavior. Mice lacking D2 receptors show parkinsonian symptoms (Baik et al. 1995xParkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Baik, J.H., Picetti, R., Saiardi, A., Thiriet, G., Dierich, A., Depaulis, A., Le Meur, M., and Borrelli, E. Nature. 1995; 377: 424–428

Crossref | PubMedSee all ReferencesBaik et al. 1995), as do normal animals given D2 antagonists. Dopaminergic drugs effective in the treatment of Parkinson's disease vary in their efficacy at D1 receptors, but they all cause stimulation of D2 receptors (Cummings 1991xBehavioral complications of drug treatment of Parkinson's disease. Cummings, J.L. J. Am. Geriatr. Soc. 1991; 39: 708–716

Crossref | PubMedSee all ReferencesCummings 1991). Administration of D2 antagonists, or dopamine depletion with reserpine, causes disinhibition of the cAMP/PKA/CREB pathway and induction of immediate-early genes (IEGs) in D2 cells (58xD2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons. Dragunow, M., Robertson, G.S., Faull, R.L., Robertson, H.A., and Jansen, K. Neuroscience. 1990; 37: 287–294

Crossref | PubMedSee all References, 202xD1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons. Robertson, G.S., Vincent, S.R., and Fibiger, H.C. Neuroscience. 1992; 49: 285–296

Crossref | PubMedSee all References, 126xHaloperidol-induced Fos expression in striatum is dependent upon transcription factor cyclic AMP response element binding protein. Konradi, C. and Heckers, S. Neuroscience. 1995; 65: 1051–1061

Crossref | PubMed | Scopus (50)See all References, 1xLoss of haloperidol-induced gene expression and catalepsy in protein kinase A-deficient mice. Adams, M.R., Brandon, E.P., Chartoff, E.H., Idzerda, R.L., Dorsa, D.M., and McKnight, G.S. Proc. Natl. Acad. Sci. USA. 1997; 94: 12157–12161

Crossref | PubMed | Scopus (86)See all References). This is blocked by coadministered D2 agonists but not D1 agonists (58xD2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons. Dragunow, M., Robertson, G.S., Faull, R.L., Robertson, H.A., and Jansen, K. Neuroscience. 1990; 37: 287–294

Crossref | PubMedSee all References, 43xReserpine increases Fos activity in the rat basal ganglia via a quinpirole-sensitive mechanism. Cole, D.G. and Di Figlia, M. Neuroscience. 1994; 60: 115–123

Crossref | PubMed | Scopus (21)See all References).

D1 receptor stimulation leads to phosphorylation of striatal ion channels (including calcium, sodium, and potassium channels and NMDA receptors), with complex effects on cell firing that depend, in part, on the activation state of the neuron (250xD1 and D2 dopamine receptor modulation of sodium and potassium currents in rat neostriatal neurons. Surmeier, D.J. and Kitai, S.T. Prog. Brain Res. 1993; 99: 309–324

Crossref | PubMedSee all References, 93xD1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca²⁺ conductance. Hernandez-Lopez, S., Bargas, J., Surmeier, D.J., Reyes, A., and Galarraga, E. J. Neurosci. 1997; 17: 3334–3342

PubMedSee all References, 38xDopaminergic modulation of NMDA-induced whole cell currents in neostriatal neurons in slices (contribution of calcium conductances) . Cepeda, C., Colwell, C.S., Itri, J.N., Chandler, S.H., and Levine, M.S. J. Neurophysiol. 1998; 79: 82–94

PubMedSee all References, 30xVoltage-dependent neuromodulation of Na⁺ channels by D1-like dopamine receptors in rat hippocampal neurons. Cantrell, A.R., Scheuer, T., and Catterall, W.A. J. Neurosci. 1999; 19: 5301–5310

PubMedSee all References). Mice lacking D1 receptors do not show parkinsonian symptoms or other gross motor abnormalities (57xAltered striatal function in a mutant mouse lacking D1A dopamine receptors. Drago, J., Gerfen, C.R., Lachowicz, J.E., Steiner, H., Hollon, T.R., Love, P.E., Ooi, G.T., Grinberg, A., Lee, E.J., Huang, S.P. et al. Proc. Natl. Acad. Sci. USA. 1994; 91: 12564–12568

Crossref | PubMedSee all References, 281xElimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice. Xu, M., Hu, X.T., Cooper, D.C., Moratalla, R., Graybiel, A.M., White, F.J., and Tonegawa, S. Cell. 1994; 79: 945–955

Abstract | Full Text PDF | PubMedSee all References), suggesting that D2 receptor stimulation may be more essential for the enabling role of striatal dopamine on behavior. D1 receptors may have a greater role in the effects of dopamine on learning (see below; Beninger and Miller 1998xDopamine D1-like receptors and reward-related incentive learning. Beninger, R.J. and Miller, R. Neurosci. Biobehav. Rev. 1998; 22: 335–345

Crossref | PubMed | Scopus (173)See all ReferencesBeninger and Miller 1998). However, activation of both D1 and D2 receptors can have synergistic effects on acute neural activity, gene expression, and behavior (182xD1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease. Paul, M.L., Graybiel, A.M., David, J.C., and Robertson, H.A. J. Neurosci. 1992; 12: 3729–3742

PubMedSee all References, 139xStriatal Fos expression is indicative of dopamine D1/D2 synergism and receptor supersensitivity. LaHoste, G.J., Yu, J., and Marshall, J.F. Proc. Natl. Acad. Sci. USA. 1993; 90: 7451–7455

Crossref | PubMedSee all References, 78xD1 and D2 dopamine receptor function in the striatum (coactivation of D1- and D2-dopamine receptors on separate populations of neurons results in potentiated immediate early gene response in D1-containing neurons) . Gerfen, C.R., Keefe, K.A., and Gauda, E.B. J. Neurosci. 1995; 15: 8167–8176

PubMedSee all References, 99xDopamine enhances glutamate-induced excitation of rat striatal neurons by cooperative activation of D1 and D2 class receptors. Hu, X.T. and White, F.J. Neurosci. Lett. 1997; 224: 61–65

Crossref | PubMed | Scopus (75)See all References). The activating effect of increased striatal dopamine release on behavior may result in part from coordinated actions of D1 and D2 receptor stimulation on “direct” and “indirect” basal ganglia pathways, respectively (Wise et al. 1996xThe frontal cortex-basal ganglia system in primates. Wise, S.P., Murray, E.A., and Gerfen, C.R. Crit. Rev. Neurobiol. 1996; 10: 317–356

Crossref | PubMedSee all ReferencesWise et al. 1996), although the exact nature of the information processing achieved through these circuits remains unclear.

Intracellular signaling produced by D1 receptor stimulation can cause a variety of cellular responses, with varying time courses. Some of these changes cause altered sensitivity to neurotransmitters and may therefore be involved in altered behavioral responses to drugs. For example, phosphorylation and internalization of striatal D1 receptors can occur within minutes of exposure to amphetamine or D1 agonists and are associated with a diminished cAMP response to subsequent D1 stimulation (e.g., 210xAcute in vivo amphetamine produces a homologous desensitization of dopamine receptor-coupled adenylate cyclase activities and decreases agonist binding to the D1 site. Roseboom, P.H. and Gnegy, M.E. Mol. Pharmacol. 1989; 35: 139–147

PubMedSee all References, 253xDifferential regulation of dopamine D1A receptor responsiveness by various G protein-coupled receptor kinases. Tiberi, M., Nash, S.R., Bertrand, L., Lefkowitz, R.J., and Caron, M.G. J. Biol. Chem. 1996; 271: 3771–3778

Crossref | PubMed | Scopus (122)See all References, 59xInternalization of D1 dopamine receptor in striatal neurons in vivo as evidence of activation by dopamine agonists. Dumartin, B., Caille, I., Gonon, F., and Bloch, B. J. Neurosci. 1998; 18: 1650–1661

PubMedSee all References). This type of rapid adaptation may be responsible for the first cocaine administration in a “binge” having the largest subjective and physiological D1 effects (“acute tolerance”). Longer-lasting changes in dopamine neurotransmission can be achieved through altered gene expression. For example, prolonged activation of D1 receptors can lead to increased expression of the neuropeptide dynorphin in striatal D1 cells (77xD1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Gerfen, C.R., Engber, T.M., Mahan, L.C., Susel, Z., Chase, T.N., Monsma, F.J. Jr., and Sibley, D.R. Science. 1990; 250: 1429–1432

Crossref | PubMedSee all References, 46xNeuronal adaptation to amphetamine and dopamine (molecular mechanisms of prodynorphin gene regulation in rat striatum) . Cole, R.L., Konradi, C., Douglass, J., and Hyman, S.E. Neuron. 1995; 14: 813–823

Abstract | Full Text PDF | PubMedSee all References). Increased dynorphin precursor mRNA is also seen in the striata of human cocaine abusers postmortem (Hurd and Herkenham 1993xMolecular alterations in the neostriatum of human cocaine addicts. Hurd, Y.L. and Herkenham, M. Synapse. 1993; 13: 357–369

Crossref | PubMedSee all ReferencesHurd and Herkenham 1993). Dynorphin activates κ opioid receptors on presynaptic dopamine terminals, causing decreased dopamine release (Spanagel et al. 1992xOpposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Spanagel, R., Herz, A., and Shippenberg, T.S. Proc. Natl. Acad. Sci. USA. 1992; 89: 2046–2050

Crossref | PubMedSee all ReferencesSpanagel et al. 1992). Thus, some effects of psychostimulants on gene expression appear to be compensatory adaptations to excessive stimulation of neurotransmitter receptors. Following an extended period of cocaine self-administration, extracellular levels of dopamine are depressed below normal baseline levels (Weiss et al. 1992xBasal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration. Weiss, F., Markou, A., Lorang, M.T., and Koob, G.F. Brain Res. 1992; 593: 314–318

Crossref | PubMedSee all ReferencesWeiss et al. 1992). Increases in dynorphin expression may be one of the mechanisms involved in this blunting of normal dopamine neurotransmission (Steiner and Gerfen 1996xDynorphin regulates D1 dopamine receptor-mediated responses in the striatum (relative contributions of pre- and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene induction) . Steiner, H. and Gerfen, C.R. J. Comp. Neurol. 1996; 376: 530–541

Crossref | PubMedSee all ReferencesSteiner and Gerfen 1996). κ receptor agonists are aversive in both humans and rats (Shippenberg et al. 1993xExamination of the neurochemical substrates mediating the motivational effects of opioids (role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors) . Shippenberg, T.S., Bals-Kubik, R., and Herz, A. J. Pharmacol. Exp. Ther. 1993; 265: 53–59

PubMedSee all ReferencesShippenberg et al. 1993), so an increase in dynorphin expression due to psychostimulant administration may contribute to the dysphoria seen during withdrawal (Shippenberg and Rea 1997xSensitization to the behavioral effects of cocaine (modulation by dynorphin and kappa-opioid receptor agonists) . Shippenberg, T.S. and Rea, W. Pharmacol. Biochem. Behav. 1997; 57: 449–455

Crossref | PubMed | Scopus (95)See all ReferencesShippenberg and Rea 1997). Dopamine-induced increases in dynorphin expression require prolonged stimulation of D1 receptors (J. D. B. and S. E. H., unpublished data) and increased phosphorylation of CREB (Cole et al. 1995xNeuronal adaptation to amphetamine and dopamine (molecular mechanisms of prodynorphin gene regulation in rat striatum) . Cole, R.L., Konradi, C., Douglass, J., and Hyman, S.E. Neuron. 1995; 14: 813–823

Abstract | Full Text PDF | PubMedSee all ReferencesCole et al. 1995). Prolonged overexpression of phospho-CREB in the ventral striatum via a viral vector also increases dynorphin expression and reduces the rewarding effects of cocaine (Carlezon et al. 1998xRegulation of cocaine reward by CREB. Carlezon, W.A. Jr., Thome, J., Olson, V.G., Lane-Ladd, S.B., Brodkin, E.S., Hiroi, N., Duman, R.S., Neve, R.L., and Nestler, E.J. Science. 1998; 282: 2272–2275

Crossref | PubMed | Scopus (461)See all ReferencesCarlezon et al. 1998). The increase in striatal dynorphin mRNA levels is one of the longest-lasting of the dozens of mRNA changes induced by cocaine or D1 agonists (243xRegulation of kappa opioid receptor mRNA in the rat brain by “binge” pattern cocaine administration and correlation with preprodynorphin mRNA. Spangler, R., Ho, A., Zhou, Y., Maggos, C.E., Yuferov, V., and Kreek, M.J. Brain Res. Mol. Brain Res. 1996; 38: 71–76

Crossref | PubMed | Scopus (76)See all References, 15xA complex program of striatal gene expression induced by dopaminergic stimulation. Berke, J.D., Paletzki, R.F., Aronson, G.J., Hyman, S.E., and Gerfen, C.R. J. Neurosci. 1998; 18: 5301–5310

PubMedSee all References), yet even this increase fades within days if no further drugs are administered. Thus, the upregulation of striatal dynorphin by psychostimulants is an example of a reversible homeostatic adaptation that may contribute to withdrawal symptoms. The set of withdrawal symptoms produced by a given addictive drug result from multiple such homeostatic responses, in multiple brain regions (195xOpiate withdrawal and the rat locus coeruleus (behavioral, electrophysiological, and biochemical correlates) . Rasmussen, K., Beitner-Johnson, D.B., Krystal, J.H., Aghajanian, G.K., and Nestler, E.J. J. Neurosci. 1990; 10: 2308–2317

PubMedSee all References, 102xAddiction to cocaine and amphetamine. Hyman, S.E. Neuron. 1996; 16: 901–904

Abstract | Full Text | Full Text PDF | PubMed | Scopus (161)See all References, 131xNeuroscience of addiction. Koob, G.F., Sanna, P.P., and Bloom, F.E. Neuron. 1998; 21: 467–476

Abstract | Full Text | Full Text PDF | PubMed | Scopus (624)See all References, 284xWhole-cell plasticity in cocaine withdrawal (reduced sodium currents in nucleus accumbens neurons) . Zhang, X.F., Hu, X.T., and White, F.J. J. Neurosci. 1998; 18: 488–498

PubMedSee all References). When drug administration ceases, these neural systems gradually return to their normal sensitivity. This can take anywhere from minutes to weeks depending on the particular homeostatic response, but so far none appears sufficiently long-lasting to be involved in the persistent tendency of addicted individuals to relapse.

The idea that changes in behavioral responses to psychostimulants reflect altered dopamine neurotransmission is attractively straightforward and has been extensively investigated. Psychostimulants can evoke a wide range of changes in both midbrain dopamine neurons and their forebrain targets (Self and Nestler 1995xMolecular mechanisms of drug reinforcement and addiction. Self, D.W. and Nestler, E.J. Annu. Rev. Neurosci. 1995; 18: 463–495

Crossref | PubMedSee all ReferencesSelf and Nestler 1995); a subset of these likely contribute to some forms of sensitization. For example, after a period of psychostimulant administration, the ability of a subsequent dose to evoke dopamine release in the striatum can be increased (for reviews, see 110xDopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Kalivas, P.W. and Stewart, J. Brain Res. Brain Res. Rev. 1991; 16: 223–244

Crossref | PubMed | Scopus (1356)See all References, 205xEnduring changes in brain and behavior produced by chronic amphetamine administration (a review and evaluation of animal models of amphetamine psychosis) . Robinson, T.E. and Becker, J.B. Brain Res. 1986; 396: 157–198

Crossref | PubMedSee all References). This effect can persist for at least several weeks (e.g., 208xLong-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine (sex differences) . Robinson, T.E., Becker, J.B., and Presty, S.K. Brain Res. 1982; 253: 231–241

Crossref | PubMedSee all References, 109xTime course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. Kalivas, P.W. and Duffy, P. J. Neurosci. 1993; 13: 266–275

PubMedSee all References, 96xBehavioral and neurochemical sensitization following cocaine self- administration. Hooks, M.S., Duffy, P., Striplin, C., and Kalivas, P.W. Psychopharmacology (Berl.). 1994; 115: 265–272

Crossref | PubMed | Scopus (90)See all References). Injections of amphetamine or D1 agonists directly into the vicinity of midbrain dopamine cells can also lead to an enhanced ability of subsequent doses of psychostimulants to cause dopamine release from terminals in the striatum (111xAmphetamine injection into the ventral mesencephalon sensitizes rats to peripheral amphetamine and cocaine. Kalivas, P.W. and Weber, B. J. Pharmacol. Exp. Ther. 1988; 245: 1095–1102

PubMedSee all References, 258xAmphetamine injected into the ventral tegmental area sensitizes the nucleus accumbens dopaminergic response to systemic amphetamine (an in vivo microdialysis study in the rat) . Vezina, P. Brain Res. 1993; 605: 332–337

Crossref | PubMed | Scopus (124)See all References, 259xD1 dopamine receptor activation is necessary for the induction of sensitization by amphetamine in the ventral tegmental area. Vezina, P. J. Neurosci. 1996; 16: 2411–2420

PubMedSee all References, 191xRepeated intra-ventral tegmental area administration of SKF-38393 induces behavioral and neurochemical sensitization to a subsequent cocaine challenge. Pierce, R.C., Born, B., Adams, M., and Kalivas, P.W. J. Pharmacol. Exp. Ther. 1996; 278: 384–392

PubMedSee all References). Enhanced dopamine release can be observed even in dissociated striatal slices and may involve alterations to signal transduction pathways in dopamine terminals (e.g., Kantor et al. 1999xEnhanced amphetamine- and K⁺-mediated dopamine release in rat striatum after repeated amphetamine (differential requirements for Ca²⁺- and calmodulin-dependent phosphorylation and synaptic vesicles) . Kantor, L., Hewlett, G.H., and Gnegy, M.E. J. Neurosci. 1999; 19: 3801–3808

PubMedSee all ReferencesKantor et al. 1999).

Other behavioral manipulations, notably stress or social isolation, can also enhance the locomotor effects of subsequent doses of psychostimulants (213xThe effects of psychomotor stimulants on stereotypy and locomotor activity in socially-deprived and control rats. Sahakian, B.J., Robbins, T.W., Morgan, M.J., and Iversen, S.D. Brain Res. 1975; 84: 195–205

Crossref | PubMed | Scopus (128)See all References, 187xPathophysiological basis of vulnerability to drug abuse (role of an interaction between stress, glucocorticoids, and dopaminergic neurons) . Piazza, P.V. and Le Moal, M.L. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 359–378

Crossref | PubMedSee all References). Stress-induced sensitization occurs most readily when the stressor is unpredictable and/or uncontrollable (146xCoping and the stress-induced potentiation of stimulant stereotypy in the rat. MacLennan, A.J. and Maier, S.F. Science. 1983; 219: 1091–1093

Crossref | PubMedSee all References, 79xNon-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. Goeders, N.E. and Guerin, G.F. Psychopharmacology. 1994; 114: 63–70

Crossref | PubMedSee all References). Components of stress pathways may also be important in the development of some forms of psychostimulant sensitization (52xStress-induced sensitization and glucocorticoids. I. Sensitization of dopamine-dependent locomotor effects of amphetamine and morphine depends on stress-induced corticosterone secretion. Deroche, V., Marinelli, M., Maccari, S., Le Moal, M., Simon, H., and Piazza, P.V. J. Neurosci. 1995; 15: 7181–7188

PubMedSee all References, 212xIndividual differences in stress-induced dopamine release in the nucleus accumbens are influenced by corticosterone. Rouge-Pont, F., Deroche, V., Le Moal, M., and Piazza, P.V. Eur. J. Neurosci. 1998; 10: 3903–3907

Crossref | PubMed | Scopus (111)See all References). Psychostimulant injections cause increased levels of stress hormones such as glucocorticoids, which may produce adaptations in midbrain dopamine neurons, leading to enhanced subsequent release of dopamine (Piazza and Le Moal 1996xPathophysiological basis of vulnerability to drug abuse (role of an interaction between stress, glucocorticoids, and dopaminergic neurons) . Piazza, P.V. and Le Moal, M.L. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 359–378

Crossref | PubMedSee all ReferencesPiazza and Le Moal 1996).

However, behavioral sensitization to psychostimulants can occur without increased striatal dopamine release (e.g., 228xIn vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment. Segal, D.S. and Kuczenski, R. Brain Res. 1992; 571: 330–337

Crossref | PubMed | Scopus (137)See all References, 229xRepeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens. Segal, D.S. and Kuczenski, R. Brain Res. 1992; 577: 351–355

Crossref | PubMed | Scopus (122)See all References, 109xTime course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. Kalivas, P.W. and Duffy, P. J. Neurosci. 1993; 13: 266–275

PubMedSee all References, 89xRole of extracellular dopamine in the initiation and long-term expression of behavioral sensitization to cocaine. Heidbreder, C.A., Thompson, A.C., and Shippenberg, T.S. J. Pharmacol. Exp. Ther. 1996; 278: 490–502

PubMedSee all References, 135xBehavioral sensitization and extracellular dopamine responses to amphetamine after various treatments. Kuczenski, R., Segal, D.S., and Todd, P.K. Psychopharmacology (Berl.). 1997; 134: 221–229

Crossref | PubMed | Scopus (53)See all References). In addition, behavioral sensitization to direct dopamine agonists occurs even when the dopamine projection to forebrain is absent. In 6-OHDA-lesioned rodents, repeated administration of L-DOPA or dopamine agonists causes a progressively enhanced locomotor response to these drugs (“priming”; e.g., 107xChronic pharmacological manipulation of dopamine receptors in brain. Jenner, P. and Marsden, C.D. Neuropharmacology. 1987; 26: 931–940

Crossref | PubMedSee all References, 166xAgonist-induced homologous and heterologous sensitization to D-1- and D-2-dependent contraversive turning. Morelli, M. and Di Chiara, G. Eur. J. Pharmacol. 1987; 141: 101–107

Crossref | PubMedSee all References, 31xChronic L-dopa treatment in the unilateral 6-OHDA rat (evidence for behavioral sensitization and biochemical tolerance) . Carey, R.J. Brain Res. 1991; 568: 205–214

Crossref | PubMedSee all References). This effect may contribute to the dyskinesias, response fluctuations, and psychotic symptoms experienced by most human patients receiving long-term L-DOPA therapy for Parkinson's disease (49xBehavioral complications of drug treatment of Parkinson's disease. Cummings, J.L. J. Am. Geriatr. Soc. 1991; 39: 708–716

Crossref | PubMedSee all References, 175xAn algorithm (decision tree) for the management of Parkinson's disease (treatment guidelines. American Academy of Neurology) . Olanow, C.W. and Koller, W.C. Neurology. 1998; 50: S1–S57

Crossref | PubMedSee all References). Like psychostimulant sensitization, priming can persist for many months in the absence of drugs (e.g., Criswell et al. 1989xPriming of D1-dopamine receptor responses (long-lasting behavioral supersensitivity to a D1-dopamine agonist following repeated administration to neonatal 6-OHDA-lesioned rats) . Criswell, H., Mueller, R.A., and Breese, G.R. J. Neurosci. 1989; 9: 125–133

PubMedSee all ReferencesCriswell et al. 1989).

Alterations in postsynaptic responsiveness to dopamine may be involved in some forms of sensitization (for review, see Nestler et al. 1996xMolecular mechanisms of drug addiction (adaptations in signal transduction pathways) . Nestler, E.J., Berhow, M.T., and Brodkin, E.S. Mol. Psychiatry. 1996; 1: 190–199

PubMedSee all ReferencesNestler et al. 1996). Although psychostimulant sensitization is not consistently correlated with lasting changes in dopamine receptor mRNA or protein levels (e.g., Meador-Woodruff et al. 1993xEffects of cocaine on dopamine receptor gene expression (a study in the postmortem human brain) . Meador-Woodruff, J.H., Little, K.Y., Damask, S.P., Mansour, A., and Watson, S.J. Biol. Psychiatry. 1993; 34: 348–355

Abstract | Full Text PDF | PubMed | Scopus (27)See all ReferencesMeador-Woodruff et al. 1993), psychostimulants can cause changes in levels of G proteins and other components of intracellular signaling pathways (252xA general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Terwilliger, R.Z., Beitner-Johnson, D., Sevarino, K.A., Crain, S.M., and Nestler, E.J. Brain Res. 1991; 548: 100–110

Crossref | PubMedSee all References, 249xRobustness of G protein changes in cocaine sensitization shown with immunoblotting. Striplin, C.D. and Kalivas, P.W. Synapse. 1993; 14: 10–15

Crossref | PubMedSee all References). For example, multiple components of the cyclic AMP signaling pathway are upregulated by psychostimulants (252xA general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Terwilliger, R.Z., Beitner-Johnson, D., Sevarino, K.A., Crain, S.M., and Nestler, E.J. Brain Res. 1991; 548: 100–110

Crossref | PubMedSee all References, 168xMolecular mechanisms of drug addiction (adaptations in signal transduction pathways) . Nestler, E.J., Berhow, M.T., and Brodkin, E.S. Mol. Psychiatry. 1996; 1: 190–199

PubMedSee all References). Such observations may explain reports of increased coupling of D1 receptors to adenylate cyclase (e.g., Sala et al. 1995xBehavioral and biochemical evidence of opioidergic involvement in cocaine sensitization. Sala, M., Braida, D., Colombo, M., Groppetti, A., Sacco, S., Gori, E., and Parenti, M. J. Pharmacol. Exp. Ther. 1995; 274: 450–457

PubMedSee all ReferencesSala et al. 1995). At the electrophysiological level, it is also known that the ability of cocaine or D1 agonists to inhibit glutamate-evoked firing of striatal neurons in anesthetized rats can be enhanced by prior cocaine treatment (91xRepeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. Henry, D.J. and White, F.J. J. Pharmacol. Exp. Ther. 1991; 258: 882–890

PubMedSee all References, 92xThe persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons. Henry, D.J. and White, F.J. J. Neurosci. 1995; 15: 6287–6299

PubMedSee all References), and this change can be observed for 1 month after the last cocaine injection.

Just as increased dynorphin expression is thought to contribute to behavioral tolerance and withdrawal, physiological changes underlying persistent sensitization and addiction might be due to persistent changes in gene expression. Psychostimulants can cause the induction of a large number of genes in striatal D1 cells (45xD1 dopamine receptor activation of multiple transcription factor genes in rat striatum. Cole, A.J., Bhat, R.V., Patt, C., Worley, P.F., and Baraban, J.M. J. Neurochem. 1992; 58: 1420–1426

Crossref | PubMedSee all References, 56xPCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. Douglass, J., McKinzie, A.A., and Couceyro, P. J. Neurosci. 1995; 15: 2471–2481

PubMedSee all References, 15xA complex program of striatal gene expression induced by dopaminergic stimulation. Berke, J.D., Paletzki, R.F., Aronson, G.J., Hyman, S.E., and Gerfen, C.R. J. Neurosci. 1998; 18: 5301–5310

PubMedSee all References). However, this induction seems to be transient, with most mRNAs returning to baseline expression within a few hours to a day (264xA single injection of amphetamine or methamphetamine induces dynamic alterations in c-fos, zif/268 and preprodynorphin messenger RNA expression in rat forebrain. Wang, J.Q., Smith, A.J., and McGinty, J.F. Neuroscience. 1995; 68: 83–95

Crossref | PubMed | Scopus (99)See all References, 15xA complex program of striatal gene expression induced by dopaminergic stimulation. Berke, J.D., Paletzki, R.F., Aronson, G.J., Hyman, S.E., and Gerfen, C.R. J. Neurosci. 1998; 18: 5301–5310

PubMedSee all References). Certain protein products of psychostimulant-induced genes can persist longer in striatum (Cha et al. 1997xNAC-1, a rat brain mRNA, is increased in the nucleus accumbens three weeks after chronic cocaine self-administration. Cha, X.Y., Pierce, R.C., Kalivas, P.W., and Mackler, S.A. J. Neurosci. 1997; 17: 6864–6871

PubMedSee all ReferencesCha et al. 1997). To date the longest-lived known are posttranslationally modified products of the fosB gene, referred to as “chronic Fos-related antigens” (chronic FRAs; Hope et al. 1994xInduction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Hope, B.T., Nye, H.E., Kelz, M.B., Self, D.W., Iadarola, M.J., Nakabeppu, Y., Duman, R.S., and Nestler, E.J. Neuron. 1994; 13: 1235–1244

Abstract | Full Text PDF | PubMed | Scopus (386)See all ReferencesHope et al. 1994). These have been shown to exhibit increased levels for up to 4 weeks and may alter the ability of subsequent stimuli to induce genes regulated by AP-1 transcription factors; thus, they could alter subsequent patterns of psychostimulant-induced gene expression. Overexpression of ΔFosB in the striatum of transgenic mice is correlated with altered behavioral sensitivity to cocaine (Kelz et al. 1999xExpression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Kelz, M.B., Chen, J., Carlezon, W.A. Jr., Whisler, K., Gilden, L., Beckmann, A.M., Steffen, C., Zhang, Y.J., Marotti, L., Self, D.W. et al. Nature. 1999; 401: 272–276

Crossref | PubMed | Scopus (368)See all ReferencesKelz et al. 1999). Overall, however, there is no evidence to date for up- or downregulated mRNA or protein levels in the brain that last long enough to account for the persistence of some forms of sensitization—and in humans, addiction.

If long-term changes in gene expression are important, it is not as a result of altering dopamine release or postsynaptic dopamine sensitivity alone. Enhancing dopamine neurotransmission in striatum, which appears to lack spatial specificity, would be expected to enhance the behavioral response to psychostimulants irrespective of any specific behavioral situation. It is not therefore obvious how such mechanisms could account for the observations that both sensitization and drug taking can come under the control of specific cues (for a thorough experimental analysis of context-dependent sensitization, see Anagnostaras and Robinson 1996xSensitization to the psychomotor stimulant effects of amphetamine (modulation by associative learning) . Anagnostaras, S.G. and Robinson, T.E. Behav. Neurosci. 1996; 110: 1397–1414

Crossref | PubMed | Scopus (199)See all ReferencesAnagnostaras and Robinson 1996).

When the acute behavioral effects of psychostimulants occur in association with specific (especially novel) cues, there is an opportunity for the animal to learn this association. Most reports cited above of neurochemical or neurophysiological changes with repeated psychostimulant injections used drug administration paradigms (such as injections in the home cage) that avoid pairing drug infusions with distinct contexts. Such unpredictable drug injections may preferentially evoke nonassociative forms of sensitization.

For context-dependent sensitization and for addiction, a state in which cues can initiate complex foraging and drug-taking behaviors, additional or alternative associative learning processes must be involved. It is striking that striatal D1 receptors are coupled to the cAMP/PKA/CREB intracellular cascade (127xAmphetamine regulates gene expression in rat striatum via transcription factor CREB. Konradi, C., Cole, R.L., Heckers, S., and Hyman, S.E. J. Neurosci. 1994; 14: 5623–5634

PubMedSee all References, 102xAddiction to cocaine and amphetamine. Hyman, S.E. Neuron. 1996; 16: 901–904

Abstract | Full Text | Full Text PDF | PubMed | Scopus (161)See all References), a pathway implicated in memory formation and synaptic change in species as diverse as fruit flies, mollusks, and mice (for review, see Silva et al. 1998xCREB and memory. Silva, A.J., Kogan, J.H., Frankland, P.W., and Kida, S. Annu. Rev. Neurosci. 1998; 21: 127–148

Crossref | PubMed | Scopus (760)See all ReferencesSilva et al. 1998). D1 receptors have been shown to have an important role in hippocampal long-term potentiation (LTP), the most influential current model of synaptic plasticity. In the CA1 hippocampal region, simultaneous depolarization of pre- and postsynaptic neurons leads to opening of NMDA receptors, calcium entry into the cell, and enhancement of the strength of specific synaptic connections (147xNMDA-receptor-dependent synaptic plasticity (multiple forms and mechanisms) . Malenka, R.C. and Nicoll, R.A. Trends Neurosci. 1993; 16: 521–527

Abstract | Full Text PDF | PubMed | Scopus (505)See all References, 161xCognitive neuroscience and the study of memory. Milner, B., Squire, L.R., and Kandel, E.R. Neuron. 1998; 20: 445–468

Abstract | Full Text | Full Text PDF | PubMed | Scopus (667)See all References). For LTP to persist for more than 2–3 hr (“late-phase” LTP or L-LTP) requires increases in postsynaptic cAMP, phosphorylation of CREB, gene transcription, and protein synthesis (20xDeficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schutz, G., and Silva, A.J. Cell. 1994; 79: 59–68

Abstract | Full Text PDF | PubMed | Scopus (1098)See all References, 171xRequirement of a critical period of transcription for induction of a late phase of LTP. Nguyen, P.V., Abel, T., and Kandel, E.R. Science. 1994; 265: 1104–1107

Crossref | PubMedSee all References, 72xInfluence of actinomycin D, an RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro. Frey, U., Frey, S., Schollmeier, F., and Krug, M. J. Physiol. 1996; 490: 703–711

PubMedSee all References, 170xA macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. Nguyen, P.V. and Kandel, E.R. J. Neurosci. 1996; 16: 3189–3198

PubMedSee all References). The requirement for activation of gene expression seems to be transient, since hippocampal L-LTP is disrupted by blockers of transcription or translation if they are given within a few hours of the LTP-inducing stimulus but not if given later (Frey and Morris 1997xSynaptic tagging and long-term potentiation. Frey, U. and Morris, R.G. Nature. 1997; 385: 533–536

Crossref | PubMed | Scopus (688)See all ReferencesFrey and Morris 1997). Activators of the cAMP cascade, including D1 agonists, can induce L-LTP (71xEffects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Frey, U., Huang, Y.Y., and Kandel, E.R. Science. 1993; 260: 1661–1664

Crossref | PubMedSee all References, 100xD1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus. Huang, Y.Y. and Kandel, E.R. Proc. Natl. Acad. Sci. USA. 1995; 92: 2446–2450

Crossref | PubMed | Scopus (303)See all References), and D1 agonists can prevent depotentiation of potentiated synapses (Otmakhova and Lisman 1998xD1/D5 dopamine receptors inhibit depotentiation at CA1 synapses via cAMP-dependent mechanism. Otmakhova, N.A. and Lisman, J.E. J. Neurosci. 1998; 18: 1270–1279

PubMedSee all ReferencesOtmakhova and Lisman 1998). D1 blockade blocks hippocampal L-LTP (69xDopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices. Frey, U., Schroeder, H., and Matthies, H. Brain Res. 1990; 522: 69–75

Crossref | PubMedSee all References, 70xThe effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro. Frey, U., Matthies, H., Reymann, K.G., and Matthies, H. Neurosci. Lett. 1991; 129: 111–114

Crossref | PubMedSee all References, 100xD1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus. Huang, Y.Y. and Kandel, E.R. Proc. Natl. Acad. Sci. USA. 1995; 92: 2446–2450

Crossref | PubMed | Scopus (303)See all References), and D1 knockout mice do not show L-LTP (Matthies et al. 1997xDopamine D1-deficient mutant mice do not express the late phase of hippocampal long-term potentiation. Matthies, H., Becker, A., Schroeder, H., Kraus, J., Hollt, V., and Krug, M. Neuroreport. 1997; 8: 3533–3535

Crossref | PubMedSee all ReferencesMatthies et al. 1997). In the hippocampus, therefore, D1 receptor activation may act to gate synaptic plasticity, helping to determine whether changes in synaptic strength are long lasting or merely transient. A role for dopamine receptors in the modification of synaptic strength fits well with the idea that increases in extracellular dopamine can act as a reinforcement learning signal in striatum (Wickens and Kotter 1995xCellular models of reinforcement. Wickens, J. and Kotter, R.

See all ReferencesWickens and Kotter 1995). LTP (and also LTD, long-term depression) is found at corticostriatal synapses in vivo (Charpier and Deniau 1997xIn vivo activity-dependent plasticity at cortico-striatal connections (evidence for physiological long-term potentiation) . Charpier, S. and Deniau, J.M. Proc. Natl. Acad. Sci. USA. 1997; 94: 7036–7040

Crossref | PubMed | Scopus (142)See all ReferencesCharpier and Deniau 1997) and in vitro (e.g., 125xSimultaneous LTP of non-NMDA- and LTD of NMDA-receptor-mediated responses in the nucleus accumbens. Kombian, S.B. and Malenka, R.C. Nature. 1994; 368: 242–246

Crossref | PubMed | Scopus (127)See all References, 29xAbnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. Calabresi, P., Saiardi, A., Pisani, A., Baik, J.H., Centonze, D., Mercuri, N.B., Bernardi, G., and Borrelli, E. J. Neurosci. 1997; 17: 4536–4544

PubMedSee all References). Some groups have found that striatal LTP can be modified by dopamine receptor stimulation (272xDopamine reverses the depression of rat corticostriatal synapses which normally follows high-frequency stimulation of cortex in vitro. Wickens, J.R., Begg, A.J., and Arbuthnott, G.W. Neuroscience. 1996; 70: 1–5

Crossref | PubMedSee all References, 29xAbnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. Calabresi, P., Saiardi, A., Pisani, A., Baik, J.H., Centonze, D., Mercuri, N.B., Bernardi, G., and Borrelli, E. J. Neurosci. 1997; 17: 4536–4544

PubMedSee all References; but see Pennartz et al. 1993xSynaptic plasticity in an in vitro slice preparation of the rat nucleus accumbens. Pennartz, C.M., Ameerun, R.F., Groenewegen, H.J., and Lopes da Silva, F.H. Eur. J. Neurosci. 1993; 5: 107–117

Crossref | PubMedSee all ReferencesPennartz et al. 1993). To our knowledge, however, existing studies of the effects of dopamine on striatal synaptic plasticity have only examined effects at early time points after LTP induction rather than L-LTP.

Changes in gene expression resulting from CREB phosphorylation can affect the whole neuron (Casadio et al. 1999xA transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Casadio, A., Martin, K.C., Giustetto, M., Zhu, H., Chen, M., Bartsch, D., Bailey, C.H., and Kandel, E.R. Cell. 1999; 99: 221–237

Abstract | Full Text | Full Text PDF | PubMed | Scopus (314)See all ReferencesCasadio et al. 1999), but hippocampal LTP involves change at specific synapses. To account for this, one current theory suggests that appropriate activation of a synapse sets up a “tag” that marks the synapse as eligible for long-lasting modification by a subsequent signal from the nucleus (67xSynaptic tagging and long-term potentiation. Frey, U. and Morris, R.G. Nature. 1997; 385: 533–536

Crossref | PubMed | Scopus (688)See all References, 68xSynaptic tagging (implications for late maintenance of hippocampal long-term potentiation) . Frey, U. and Morris, R.G. Trends Neurosci. 1998; 21: 181–188

Abstract | Full Text | Full Text PDF | PubMed | Scopus (297)See all References, 153xSynapse-specific, long-term facilitation of Aplysia sensory to motor synapses (a function for local protein synthesis in memory storage) . Martin, K.C., Casadio, A., Zhu, H.E.Y., Rose, J.C., Chen, M., Bailey, C.H., and Kandel, E.R. Cell. 1997; 91: 927–938

Abstract | Full Text | Full Text PDF | PubMed | Scopus (446)See all References). Theories of striatal reinforcement learning suggest that following an action, there is a period during which an “eligibility trace” allows the representation of that action to be modified if the reinforcement signal is received (e.g., 98xA model of how the basal ganglia generate and use neural signals that predict reinforcement. Houk, J.C., Adams, J.L., and Barto, A.G.

See all References, 221xThe phasic reward signal of primate dopamine neurons. Schultz, W. Adv. Pharmacol. 1998; 42: 686–690

Crossref | PubMed | Scopus (18)See all References). While there may well be multiple mechanisms acting at different time scales, one candidate mechanism for an eligibility trace is the establishment of synaptic tags, with dopamine effects on gene expression acting as the reinforcement signal.

Just as dopamine and glutamate receptors are jointly involved in hippocampal synaptic plasticity, dopamine and glutamate inputs to striatum cooperate in the induction of gene expression and behavioral change. In normal animals, selective stimulation of striatal D1 receptors alone causes only a modest induction of IEG expression (Robertson et al. 1992xD1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons. Robertson, G.S., Vincent, S.R., and Fibiger, H.C. Neuroscience. 1992; 49: 285–296

Crossref | PubMedSee all ReferencesRobertson et al. 1992). However, D1 receptor activation can increase the striatal IEG expression caused by cortical stimulation. For example, Arnauld et al. 1996xInvolvement of the caudal striatum in auditory processing (c-fos response to cortical application of picrotoxin and to auditory stimulation) . Arnauld, E., Jeantet, Y., Arsaut, J., and Demotes-Mainard, J. Brain Res. Mol. Brain Res. 1996; 41: 27–35

Crossref | PubMed | Scopus (23)See all ReferencesArnauld et al. 1996 found that a modest dose of systemic D1 agonists increased the striatal IEG response to auditory stimuli, or to direct stimulation of auditory cortex. This response was specific to areas of striatum receiving inputs from auditory cortex. Conversely, if cortical projections to striatum are severed, the striatal IEG response to amphetamine is reduced (Cenci and Bjorklund 1993xTransection of corticostriatal afferents reduces amphetamine- and apomorphine-induced striatal Fos expression and turning behaviour in unilaterally 6-hydroxydopamine-lesioned rats. Cenci, M.A. and Bjorklund, A. Eur. J. Neurosci. 1993; 5: 1062–1070

Crossref | PubMedSee all ReferencesCenci and Bjorklund 1993). Increased activity of cortical areas may also account for observations that giving an amphetamine injection in a novel environment greatly enhances the degree of both striatal IEG induction and behavioral sensitization, without affecting the extent of striatal dopamine release (Badiani et al. 1998xAmphetamine-induced behavior, dopamine release, and c-fos mRNA expression (modulation by environmental novelty) . Badiani, A., Oates, M.M., Day, H.E., Watson, S.J., Akil, H., and Robinson, T.E. J. Neurosci. 1998; 18: 10579–10593

PubMedSee all ReferencesBadiani et al. 1998).

Cocaine, amphetamine, nicotine, and morphine all cause induction of IEG expression in striatum; for each of these drugs IEG induction is blocked by either D1 antagonists or NMDA receptor antagonists (283xCocaine induces striatal c-fos-immunoreactive proteins via dopaminergic D1 receptors. Young, S.T., Porrino, L.J., and Iadarola, M.J. Proc. Natl. Acad. Sci. USA. 1991; 88: 1291–1295

Crossref | PubMedSee all References, 121xNicotine induced c-fos expression in the striatum is mediated mostly by dopamine D1 receptor and is dependent on NMDA stimulation. Kiba, H. and Jayaraman, A. Brain Res. Mol. Brain Res. 1994; 23: 1–13

Crossref | PubMedSee all References, 142xMorphine induces c-fos and junB in striatum and nucleus accumbens via D1 and N-methyl-D-aspartate receptors. Liu, J., Nickolenko, J., and Sharp, F.R. Proc. Natl. Acad. Sci. USA. 1994; 91: 8537–8541

Crossref | PubMedSee all References). Mutant mice lacking D1 receptors do not show this IEG response (Moratalla et al. 1996xCellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the D1 dopamine receptor. Moratalla, R., Xu, M., Tonegawa, S., and Graybiel, A.M. Proc. Natl. Acad. Sci. USA. 1996; 93: 14928–14933

Crossref | PubMed | Scopus (135)See all ReferencesMoratalla et al. 1996); in such mice locomotor sensitization to amphetamine is diminished and does not progressively increase with repeated injections (Crawford et al. 1997xEffects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A-deficient mouse. Crawford, C.A., Drago, J., Watson, J.B., and Levine, M.S. Neuroreport. 1997; 8: 2523–2527

Crossref | PubMedSee all ReferencesCrawford et al. 1997). Similarly, the development of psychostimulant sensitization is blocked by NMDA receptor antagonists (113xBlockade of “reverse tolerance” to cocaine and amphetamine by MK-801. Karler, R., Calder, L.D., Chaudhry, I.A., and Turkanis, S.A. Life Sci. 1989; 45: 599–606

Crossref | PubMedSee all References, 277xRepeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine. Wolf, M.E. and Khansa, M.R. Brain Res. 1991; 562: 164–168

Crossref | PubMed | Scopus (156)See all References). NMDA receptor blockade also prevents development of a conditioned locomotor response to a psychostimulant-associated environment (Wolf and Khansa 1991xRepeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine. Wolf, M.E. and Khansa, M.R. Brain Res. 1991; 562: 164–168

Crossref | PubMed | Scopus (156)See all ReferencesWolf and Khansa 1991). Infusions of NMDA antagonists into the nucleus accumbens interfere with acquisition of an operant task, in which a rat has to learn to press a lever to receive food (Kelley et al. 1997xResponse-reinforcement learning is dependent on N-methyl-D-aspartate receptor activation in the nucleus accumbens core. Kelley, A.E., Smith-Roe, S.L., and Holahan, M.R. Proc. Natl. Acad. Sci. USA. 1997; 94: 12174–12179

Crossref | PubMed | Scopus (201)See all ReferencesKelley et al. 1997). In that experiment, NMDA antagonism did not interfere with performance of a previously learned task. Similarly, doses of NMDA antagonists that prevent development of sensitization do not prevent expression of previously established psychostimulant sensitization (Karler et al. 1991xDNQX blockade of amphetamine behavioral sensitization. Karler, R., Calder, L.D., and Turkanis, S.A. Brain Res. 1991; 552: 295–300

Crossref | PubMed | Scopus (124)See all ReferencesKarler et al. 1991; for review, see Wolf 1998xThe role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Wolf, M.E. Prog. Neurobiol. 1998; 54: 679–720

Crossref | PubMed | Scopus (693)See all ReferencesWolf 1998).

As in the hippocampus, combined increases in the second messengers cAMP and calcium appear to be critical in altering striatal gene expression. In cultured striatal cells, D1 agonists cause phosphorylation of CREB and IEG expression, but this is blocked by NMDA receptor antagonists or calcium removal (128xAmphetamine- and dopamine-induced immediate early gene expression in striatal neurons depends on postsynaptic NMDA receptors and calcium. Konradi, C., Leveque, J.C., and Hyman, S.E. J. Neurosci. 1996; 16: 4231–4239

PubMedSee all References, 51xNMDA and D1 receptors regulate the phosphorylation of CREB and the induction of c-fos in striatal neurons in primary culture. Das, S., Grunert, M., Williams, L., and Vincent, S.R. Synapse. 1997; 25: 227–233

Crossref | PubMed | Scopus (89)See all References). Increased intracellular calcium can contribute to CREB phosphorylation by multiple signal transduction mechanisms (Figure 2Figure 2). Phosphorylation via mitogen-activated protein kinase (MAPK) pathways (Xing et al. 1996xCoupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Xing, J., Ginty, D.D., and Greenberg, M.E. Science. 1996; 273: 959–963

Crossref | PubMedSee all ReferencesXing et al. 1996) is thought to be important for synaptic plasticity and certain forms of learning (132xA kinase to remember (dual roles for MAP kinase in long-term memory) . Kornhauser, J.M. and Greenberg, M.E. Neuron. 1997; 18: 839–842

Abstract | Full Text | Full Text PDF | PubMed | Scopus (118)See all References, 152xMAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Martin, K.C., Michael, D., Rose, J.C., Barad, M., Casadio, A., Zhu, H., and Kandel, E.R. Neuron. 1997; 18: 899–912

Abstract | Full Text | Full Text PDF | PubMed | Scopus (372)See all References, 103xCross talk between ERK and PKA is required for Ca²⁺ stimulation of CREB-dependent transcription and ERK nuclear translocation. Impey, S., Obrietan, K., Wong, S.T., Poser, S., Yano, S., Wayman, G., Deloulme, J.C., Chan, G., and Storm, D.R. Neuron. 1998; 21: 869–883

Abstract | Full Text | Full Text PDF | PubMed | Scopus (594)See all References). Stimulation of cortex causes activation of the ERK MAPKs in striatal cells (Sgambato et al. 1998axExtracellular signal-regulated kinase (ERK) controls immediate early gene induction on corticostriatal stimulation. Sgambato, V., Pages, C., Rogard, M., Besson, M.J., and Caboche, J. J. Neurosci. 1998; 18: 8814–8825

PubMedSee all ReferencesSgambato et al. 1998a), and this is dependent on NMDA receptor stimulation and calcium entry (Vincent et al. 1998xNeurotransmitter regulation of MAP kinase signaling in striatal neurons in primary culture. Vincent, S.R., Sebben, M., Dumuis, A., and Bockaert, J. Synapse. 1998; 29: 29–36

Crossref | PubMed | Scopus (60)See all ReferencesVincent et al. 1998). ERK activation can also contribute to striatal IEG induction through phosphorylation of Elk-1 (Sgambato et al. 1998bxIn vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signaling pathway, in the adult rat brain. Sgambato, V., Vanhoutte, P., Pages, C., Rogard, M., Hipskind, R., Besson, M.J., and Caboche, J. J. Neurosci. 1998; 18: 214–226

PubMedSee all ReferencesSgambato et al. 1998b).

Psychostimulants cause the rapid, transient induction of a large number of distinct genes in striatal D1 cells (16xDopamine and glutamate agonists stimulate neuron-specific expression of Fos-like protein in the striatum. Berretta, S., Robertson, H.A., and Graybiel, A.M. J. Neurophysiol. 1992; 68: 767–777

PubMedSee all References, 45xD1 dopamine receptor activation of multiple transcription factor genes in rat striatum. Cole, A.J., Bhat, R.V., Patt, C., Worley, P.F., and Baraban, J.M. J. Neurochem. 1992; 58: 1420–1426

Crossref | PubMedSee all References, 15xA complex program of striatal gene expression induced by dopaminergic stimulation. Berke, J.D., Paletzki, R.F., Aronson, G.J., Hyman, S.E., and Gerfen, C.R. J. Neurosci. 1998; 18: 5301–5310

PubMedSee all References). Although the function of most of these genes is not yet clear, there is substantial overlap with the set of genes induced in hippocampal LTP. This includes genes such as homer-1a, narp, and arc that are potentially involved in regulation of synaptic function (e.g., 44xRapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Cole, A.J., Saffen, D.W., Baraban, J.M., and Worley, P.F. Nature. 1989; 340: 474–476

Crossref | PubMedSee all References, 282xEgr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with egr1/zif268. Yamagata, K., Kaufmann, W.E., Lanahan, A., Papapavlou, M., Barnes, C.A., Andreasson, K.I., and Worley, P.F. Learn. Mem. 1994; 1: 140–152

PubMedSee all References, 66xActivation of arc, a putative “effector” immediate early gene, by cocaine in rat brain. Fosnaugh, J.S., Bhat, R.V., Yamagata, K., Worley, P.F., and Baraban, J.M. J. Neurochem. 1995; 64: 2377–2380

Crossref | PubMedSee all References, 143xArc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Lyford, G.L., Yamagata, K., Kaufmann, W.E., Barnes, C.A., Sanders, L.K., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Lanahan, A.A., and Worley, P.F. Neuron. 1995; 14: 433–445

Abstract | Full Text PDF | PubMedSee all References, 21xHomer (a protein that selectively binds metabotropic glutamate receptors) . Brakeman, P.R., Lanahan, A.A., O'Brien, R., Roche, K., Barnes, C.A., Huganir, R.L., and Worley, P.F. Nature. 1997; 386: 284–288

Crossref | PubMed | Scopus (684)See all References, 174xSynaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp. O'Brien, R.J., Xu, D., Petralia, R.S., Steward, O., Huganir, R.L., and Worley, P. Neuron. 1999; 23: 309–323

Abstract | Full Text | Full Text PDF | PubMed | Scopus (250)See all References). In some systems, persistent alterations in behavior are associated with structural changes to synaptic connections (Bailey and Kandel 1993xStructural changes accompanying memory storage. Bailey, C.H. and Kandel, E.R. Annu. Rev. Physiol. 1993; 55: 397–426

Crossref | PubMedSee all ReferencesBailey and Kandel 1993). Similarly, the late phase of hippocampal LTP may also involve localized formation of new synaptic contacts (Engert and Bonhoeffer 1999xDendritic spine changes associated with hippocampal long-term synaptic plasticity. Engert, F. and Bonhoeffer, T. Nature. 1999; 399: 66–70

Crossref | PubMed | Scopus (948)See all ReferencesEngert and Bonhoeffer 1999). Such structural modifications may also be involved in the long-lasting effects of psychostimulants. Chronic amphetamine administration causes increased dendritic spine density in the nucleus accumbens (and also in prefrontal cortex), as well as an increased number of branched spines (Robinson and Kolb 1997xPersistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. Robinson, T.E. and Kolb, B. J. Neurosci. 1997; 17: 8491–8497

PubMedSee all ReferencesRobinson and Kolb 1997). Conversely, dopamine denervation causes a reduction in striatal dendritic spine density (104xSpine density on neostriatal neurones changes with 6-hydroxydopamine lesions and with age. Ingham, C.A., Hood, S.H., and Arbuthnott, G.W. Brain Res. 1989; 503: 334–338

Crossref | PubMedSee all References, 105xMorphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway. Ingham, C.A., Hood, S.H., van Maldegem, B., Weenink, A., and Arbuthnott, G.W. Exp. Brain Res. 1993; 93: 17–27

Crossref | PubMedSee all References, 160xEffects of dopamine depletion on the morphology of medium spiny neurons in the shell and core of the rat nucleus accumbens. Meredith, G.E., Ypma, P., and Zahm, D.S. J. Neurosci. 1995; 15: 3808–3820

PubMedSee all References) and in the number of asymmetric synapses in the striatum (Ingham et al. 1998xPlasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway. Ingham, C.A., Hood, S.H., Taggart, P., and Arbuthnott, G.W. J. Neurosci. 1998; 18: 4732–4743

PubMedSee all ReferencesIngham et al. 1998). Dopamine can stimulate neurite extension and growth cone formation in embryonic striatal cultured neurons; this action of dopamine involves D1 receptors, the cAMP/PKA pathway, and protein synthesis (219xActivation of dopaminergic D1 receptors promotes morphogenesis of developing striatal neurons. Schmidt, U., Beyer, C., Oestreicher, A.B., Reisert, I., Schilling, K., and Pilgrim, C. Neuroscience. 1996; 74: 453–460

Crossref | PubMed | Scopus (61)See all References, 220xDifferentiative effects of dopamine on striatal neurons involve stimulation of the cAMP/PKA pathway. Schmidt, U., Pilgrim, C., and Beyer, C. Mol. Cell. Neurosci. 1998; 11: 9–18

Crossref | PubMed | Scopus (37)See all References).

Addictive drugs cause dopamine release in the striatum, stimulation of D1 receptors, and induction of gene expression. D1 stimulation of gene expression is associated with long-lasting changes in synaptic efficacy and structural synaptic change. Many aspects of persistent drug-induced behavioral change may thus result from altered synaptic connectivity, without requiring persistent changes in overall neurotransmitter release, postsynaptic sensitivity, or gene expression. Despite much research on addiction and associative learning at the behavioral level, homeostatic mechanisms have been a more significant focus at the molecular and cellular level (Koob et al. 1998bxNeuroscience of addiction. Koob, G.F., Sanna, P.P., and Bloom, F.E. Neuron. 1998; 21: 467–476

Abstract | Full Text | Full Text PDF | PubMed | Scopus (624)See all ReferencesKoob et al. 1998b).

The ability of addictive drugs to engage molecular mechanisms of synaptic plasticity, and thus to alter the functioning of specific circuits, is likely to be central to their ability to reinforce and thereby establish addictive behaviors. Striatal neurons are components of brain circuits involved in the control of behavioral responses, particularly in specific contexts (224xContext-dependent activity in primate striatum reflecting past and future behavioral events. Schultz, W., Apicella, P., Romo, R., and Scarnati, E.

See all References, 275xThe frontal cortex-basal ganglia system in primates. Wise, S.P., Murray, E.A., and Gerfen, C.R. Crit. Rev. Neurobiol. 1996; 10: 317–356

Crossref | PubMedSee all References). By preferentially facilitating change at active glutamatergic striatal synapses, dopamine can reinforce an association between a particular set of stimuli and a particular behavioral response. The engagement of these striatal “habit”-learning mechanisms by addictive drugs could similarly promote a tendency for drug-related cues and contexts to provoke specific behaviors, such as drug self-administration (268xAddictive drugs as reinforcers (multiple partial actions on memory systems) . White, N.M. Addiction. 1996; 91: 921–965

Crossref | PubMed | Scopus (221)See all References, 199xDrug addiction (bad habits add up) . Robbins, T.W. and Everitt, B.J. Nature. 1999; 398: 567–570

Crossref | PubMed | Scopus (331)See all References). The development of stimulus–response habits has been attributed particularly to learning processes involving dorsal parts of striatum. Facilitation of synaptic plasticity in ventral striatum may also contribute to drug use through enhanced learning about the motivational significance of drug-related cues (Carr and White 1983xConditioned place preference from intra-accumbens but not intra-caudate amphetamine injections. Carr, G.D. and White, N.M. Life Sci. 1983; 33: 2551–2557

Crossref | PubMed | Scopus (126)See all ReferencesCarr and White 1983).

The exact nature of the relationship between associative learning and sensitization is controversial (185xConditioning as a critical determinant of sensitization induced by psychomotor stimulants. Pert, A., Post, R., and Weiss, S.R. NIDA Res. Monogr. 1990; 97: 208–241

PubMedSee all References, 247xNeurobiology of conditioning to drugs of abuse. Stewart, J. Ann. NY Acad. Sci. 1992; 654: 335–346

Crossref | PubMedSee all References, 108xAnimals predisposed to develop amphetamine self-administration show higher susceptibility to develop contextual conditioning of both amphetamine-induced hyperlocomotion and sensitization. Jodogne, C., Marinelli, M., Le Moal, M., and Piazza, P.V. Brain Res. 1994; 657: 236–244

Crossref | PubMedSee all References, 5xSensitization to the psychomotor stimulant effects of amphetamine (modulation by associative learning) . Anagnostaras, S.G. and Robinson, T.E. Behav. Neurosci. 1996; 110: 1397–1414

Crossref | PubMed | Scopus (199)See all References, 33xCocaine conditioning and cocaine sensitization (what is the relationship?) . Carey, R.J. and Gui, J. Behav. Brain Res. 1998; 92: 67–76

Crossref | PubMed | Scopus (68)See all References). One possibility is that context-dependent sensitization may arise from the acute drug enhancement of previously conditioned behavioral responses to drug-associated stimuli. Psychostimulants, nonselective dopamine agonists such as apomorphine, and specific D1 receptor agonists can all produce increases in locomotor activity that become persistently conditioned to specific contexts (241xPersistent behavioural effect in apomorphine in 6-hydroxydopamine-lesioned rats. Silverman, P.B. and Ho, B.T. Nature. 1981; 294: 475–477

Crossref | PubMedSee all References, 218xConditioned dopaminergic activity. Schiff, S.R. Biol. Psychiatry. 1982; 17: 135–154

PubMedSee all References, 164xConditioning of pre- and post-synaptic behavioural responses to the dopamine receptor agonist apomorphine in rats. Moller, H.G., Nowak, K., and Kuschinsky, K. Psychopharmacology (Berl.). 1987; 91: 50–55

Crossref | PubMedSee all References, 240xSensitization and conditioned rotation (apomorphine, quinpirole and SKF-38393 compared) . Silverman, P.B. Neuroreport. 1991; 2: 669–672

Crossref | PubMedSee all References, 179xConditioned grooming induced by the dopamine D1-like receptor agonist SKF 38393 in rats. Page, S.J. and Terry, P. Pharmacol. Biochem. Behav. 1997; 57: 829–833

Crossref | PubMed | Scopus (6)See all References). Once established, the expression of conditioned locomotor responses does not require acute dopamine release (13xPimozide blocks establishment but not expression of amphetamine-produced environment-specific conditioning. Beninger, R.J. and Hahn, B.L. Science. 1983; 220: 1304–1306

Crossref | PubMedSee all References, 24xCocaine-induced conditioned locomotion (absence of associated increases in dopamine release) . Brown, E.E. and Fibiger, H.C. Neuroscience. 1992; 48: 621–629

Crossref | PubMed | Scopus (62)See all References, 32xPavlovian conditioning of L-dopa induced movement. Carey, R.J. Psychopharmacology (Berl.). 1992; 107: 203–210

Crossref | PubMedSee all References, 26xBehavioral sensitization to cocaine, but not cocaine-conditioned behavior, is associated with increased dopamine occupation of its receptors in the nucleus accumbens. Burechailo, L. and Martin-Iverson, M.T. Behav. Neurosci. 1996; 110: 1388–1396

Crossref | PubMed | Scopus (18)See all References). However, the acute effect of a psychostimulant challenge dose will be to facilitate expression of previously established, cue-conditioned behaviors—increasing the observed locomotor effects of the drug (this effect may also be involved in the ability of low doses of addictive drugs or D2 agonists to cause reinstatement of drug self-administration; 248xRole of unconditioned and conditioned drug effects in the self- administration of opiates and stimulants. Stewart, J., de Wit, H., and Eikelboom, R. Psychol. Rev. 1984; 91: 251–268

Crossref | PubMed | Scopus (611)See all References, 231xOpposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Self, D.W., Barnhart, W.J., Lehman, D.A., and Nestler, E.J. Science. 1996; 271: 1586–1589

Crossref | PubMedSee all References).

While stimulation of striatal D1 receptors may be necessary for the acquistion of conditioned responses to psychostimulant-paired environments, it may not be sufficient. Direct amphetamine injections into striatum appear to produce neither conditioned responses nor context-dependent sensitization (55xChronic D-amphetamine in nucleus accumbens (lack of tolerance or reverse tolerance of locomotor activity) . Dougherty, G.G. Jr. and Ellinwood, E.H. Jr. Life Sci. 1981; 28: 2295–2298

Crossref | PubMedSee all References, 111xAmphetamine injection into the ventral mesencephalon sensitizes rats to peripheral amphetamine and cocaine. Kalivas, P.W. and Weber, B. J. Pharmacol. Exp. Ther. 1988; 245: 1095–1102

PubMedSee all References, 260xAmphetamine administered to the ventral tegmental area but not to the nucleus accumbens sensitizes rats to systemic morphine (lack of conditioned effects) . Vezina, P. and Stewart, J. Brain Res. 1990; 516: 99–106

Crossref | PubMed | Scopus (175)See all References). An additional drug action on midbrain dopamine cells may be involved, though how this interacts with associative learning mechanisms remains unclear.

Although molecular events are crucial, the present view of sensitization and relapse is an attempt at a systems-level explanation, involving storage of specific information in neuronal circuits. This stands in contrast to most conceptions of sensitization, in which the functioning of a brain pathway shows a general change irrespective of particular patterns of information (e.g., Pierce and Kalivas 1997xA circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Pierce, R.C. and Kalivas, P.W. Brain Res. Brain Res. Rev. 1997; 25: 192–216

Crossref | PubMed | Scopus (844)See all ReferencesPierce and Kalivas 1997). Both types of mechanism may have important roles in addiction. For example, nonassociative changes in dopamine neurotransmission may set thresholds for the effects of drugs on associative learning. Animals that have high general behavioral reactivity (indicated by a large locomotor response to a novel environment) appear to release larger amounts of dopamine into the striatum in response to stress or psychostimulants (Rouge-Pont et al. 1993xHigher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study. Rouge-Pont, F., Piazza, P.V., Kharouby, M., Le Moal, M., and Simon, H. Brain Res. 1993; 602: 169–174

Crossref | PubMedSee all ReferencesRouge-Pont et al. 1993). Such animals are more likely to acquire psychostimulant self-administration (Piazza et al. 1989xFactors that predict individual vulnerability to amphetamine self- administration. Piazza, P.V., Deminiere, J.M., Le Moal, M., and Simon, H. Science. 1989; 245: 1511–1513

Crossref | PubMedSee all ReferencesPiazza et al. 1989) and are also more likely to acquire a conditioned locomotor response to an amphetamine-associated environment (Jodogne et al. 1994xAnimals predisposed to develop amphetamine self-administration show higher susceptibility to develop contextual conditioning of both amphetamine-induced hyperlocomotion and sensitization. Jodogne, C., Marinelli, M., Le Moal, M., and Piazza, P.V. Brain Res. 1994; 657: 236–244

Crossref | PubMedSee all ReferencesJodogne et al. 1994). Once drug addiction is established, nonassociative sensitization might also serve to exacerbate the action of stressful circumstances to increase the probability of drug use (Shaham and Stewart 1995xStress reinstates heroin-seeking in drug-free animals (an effect mimicking heroin, not withdrawal) . Shaham, Y. and Stewart, J. Psychopharmacology (Berl.). 1995; 119: 334–341

Crossref | PubMed | Scopus (254)See all ReferencesShaham and Stewart 1995). Nonassociative sensitization of dopamine neurotransmission in ventral areas of striatum may be responsible for enhanced learning about the incentive/motivational properties of stimuli (e.g., Shippenberg and Heidbreder 1995xSensitization to the conditioned rewarding effects of cocaine (pharmacological and temporal characteristics) . Shippenberg, T.S. and Heidbreder, C. J. Pharmacol. Exp. Ther. 1995; 273: 808–815

PubMedSee all ReferencesShippenberg and Heidbreder 1995), and such mechanisms have been suggested to underlie addiction (Robinson and Berridge 1993xThe neural basis of drug craving (an incentive-sensitization theory of addiction) . Robinson, T.E. and Berridge, K.C. Brain Res. Brain Res. Rev. 1993; 18: 247–291

Crossref | PubMed | Scopus (3399)See all ReferencesRobinson and Berridge 1993). However it is not clear how nonassociative forms of sensitization could account for the specificity of drug self-administration—why do addictive drugs become such a focus of behavior (as opposed to, for example, food or sex)? Nonassociative sensitization mechanisms also cannot account for the specific ability of drug-associated cues to provoke drug relapse.

Associative learning is necessary for the establishment of drug-taking behavior. But is it sufficient for addiction? After all, most psychostimulant users do not become addicted (Gawin 1991xCocaine addiction (psychology and neurophysiology) . Gawin, F.H. Science. 1991; 251: 1580–1586

Crossref | PubMedSee all ReferencesGawin 1991). It is therefore important to separate the question “why do people take drugs?” from the question “why do people take drugs compulsively?” For this reason, simple drug self-administration in animals may not necessarily be a particularly good model for human addiction, though there have been recent efforts to find improved models (e.g., Ahmed and Koob 1998xTransition from moderate to excessive drug intake (change in hedonic set point) . Ahmed, S.H. and Koob, G.F. Science. 1998; 282: 298–300

Crossref | PubMed | Scopus (472)See all ReferencesAhmed and Koob 1998).

One key factor may be the unusual way in which drugs can engage synaptic plasticity. In current models of the role of dopamine in normal reinforcement learning, reinforcing events that are fully predicted do not evoke dopamine release and hence do not provoke further learning (Schultz 1998bxPredictive reward signal of dopamine neurons. Schultz, W. J. Neurophysiol. 1998; 80: 1–27

PubMedSee all ReferencesSchultz 1998b). However, the direct pharmacological actions of psychostimulants and other addictive drugs may override such normal constraints on learning (Di Chiara 1998xA motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use. Di Chiara, G. J. Psychopharmacol. 1998; 12: 54–67

Crossref | PubMed | Scopus (215)See all ReferencesDi Chiara 1998). This could lead to excessive strengthening of synaptic patterns representing drug-taking behavior, relative to other behaviors performed by the animal. To put this another way, compulsive drug use could be the result of an increasingly biased competition between behavioral options (for related ideas, see 209xThe orbitofrontal cortex. Rolls, E.T. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1996; 351: 1433–1444

Crossref | PubMedSee all References, 17xCompeting motivations (drug reinforcement vs non-drug reinforcement) . Bigelow, G.E., Brooner, R.K., and Silverman, K. J. Psychopharmacol. 1998; 12: 8–14

Crossref | PubMed | Scopus (16)See all References). Drug-addicted humans display an overall narrowing of behavioral repertoire (Koob et al. 1998axSubstance dependence as a compulsive behavior. Koob, G.F., Rocio, M., Carrera, A., Gold, L.H., Heyser, C.J., Maldonado-Irizarry, C., Markou, A., Parsons, L.H., Roberts, A.J., Schulteis, G. et al. J. Psychopharmacol. 1998; 12: 39–48

Crossref | PubMed | Scopus (41)See all ReferencesKoob et al. 1998a), with progressively more of the addict's time spent in drug-related activities.

In addition, the manner of drug intake becomes progressively more fixed—particular sequences of actions become “ritualized” and automatic (Tiffany 1990xA cognitive model of drug urges and drug-use behavior (role of automatic and nonautomatic processes) . Tiffany, S.T. Psychol. Rev. 1990; 97: 147–168

Crossref | PubMedSee all ReferencesTiffany 1990), consistent with the involvement of the dorsal striatal “habit”-learning system. Among all brain regions, it is dorsal parts of striatum that show the most robust and consistent induction of IEGs following a wide range of addictive drugs (for review, see Harlan and Garcia 1998xDrugs of abuse and immediate-early genes in the forebrain. Harlan, R.E. and Garcia, M.M. Mol. Neurobiol. 1998; 16: 221–267

Crossref | PubMedSee all ReferencesHarlan and Garcia 1998). Loss of control over drug taking may therefore arise from excessive synaptic plasticity in a neural system used to perform actions without the need for deliberate, attentive control. In normal learning, behavioral flexibility can be achieved by overriding automatic responses that have become inappropriate; this executive process is thought to involve prefrontal cortex (e.g., Goldman-Rakic 1987xCircuitry of primate prefrontal cortex and regulation of behavior by representational memory. Goldman-Rakic, P.S.

See all ReferencesGoldman-Rakic 1987). The abnormal strengthening of drug-taking behaviors may make this progressively more difficult.

The activation of synaptic plasticity is tightly regulated by numerous intracellular mechanisms. Simulations of associative learning in neural networks indicate that if synaptic plasticity occurs too readily, new learning can interfere with previously stored representations (e.g., 155xWhy there are complementary learning systems in the hippocampus and neocortex (insights from the successes and failures of connectionist models of learning and memory) . McClelland, J.L., McNaughton, B.L., and O'Reilly, R.C. Psychol. Rev. 1995; 102: 419–457

Crossref | PubMedSee all References, 87xA computational model of the progression of Alzheimer's disease. Hasselmo, M.E. MD Comput. 1997; 14: 181–191

PubMedSee all References). Such mechanisms have been proposed to be involved in the pathogenesis of schizophrenia (Greenstein-Messica and Ruppin 1998xSynaptic runaway in associative networks and the pathogenesis of schizophrenia. Greenstein-Messica, A. and Ruppin, E. Neural Comput. 1998; 10: 451–465

Crossref | PubMedSee all ReferencesGreenstein-Messica and Ruppin 1998). Psychostimulants can cause abnormally strong and prolonged release of neurotransmitters. The diminished specificity of synaptic plasticity induced by psychostimulants may be another factor contributing to the narrowing of behavioral repertoire.

Modern conceptions of learning and memory recognize the importance of multiple, semi-independent brain circuits (e.g., 157xA triple dissociation of memory systems (hippocampus, amygdala, and dorsal striatum) . McDonald, R.J. and White, N.M. Behav. Neurosci. 1993; 107: 3–22

Crossref | PubMedSee all References, 161xCognitive neuroscience and the study of memory. Milner, B., Squire, L.R., and Kandel, E.R. Neuron. 1998; 20: 445–468

Abstract | Full Text | Full Text PDF | PubMed | Scopus (667)See all References). Though interconnected, these different circuits contribute to distinct aspects of behavior. We have focused on the role of brain circuits involving the striatum, for the many reasons discussed above. However, addictive drugs likely engage learning mechanisms in many brain regions. These include other targets of dopamine innervation such as hippocampus, amygdala, and prefrontal cortex (Goldman-Rakic 1995xCellular basis of working memory. Goldman-Rakic, P.S. Neuron. 1995; 14: 477–485

Abstract | Full Text PDF | PubMedSee all ReferencesGoldman-Rakic 1995). The contributions of multiple memory circuits to addiction has been the subject of an extensive recent review (White 1996xAddictive drugs as reinforcers (multiple partial actions on memory systems) . White, N.M. Addiction. 1996; 91: 921–965

Crossref | PubMed | Scopus (221)See all ReferencesWhite 1996).

An unexpected “rewarding” event provokes multiple forms of learning, each of which contributes to the overall “reinforcing” effects of that event (270xThe psychobiology of reinforcers. White, N.M. and Milner, P.M. Annu. Rev. Psychol. 1992; 43: 443–471

Crossref | PubMedSee all References, 198xNeurobehavioural mechanisms of reward and motivation. Robbins, T.W. and Everitt, B.J. Curr. Opin. Neurobiol. 1996; 6: 228–236

Crossref | PubMed | Scopus (712)See all References). These include stimulus–response learning, assignment of emotional significance to cues and contexts associated with the rewarding event, and an enhanced explicit memory for the episode in which the event occurred. As a given task is repeatedly performed, the neural circuits most important for performing the task may change, reflecting a shift in behavioral strategy (McDonald and White 1993xA triple dissociation of memory systems (hippocampus, amygdala, and dorsal striatum) . McDonald, R.J. and White, N.M. Behav. Neurosci. 1993; 107: 3–22

Crossref | PubMedSee all ReferencesMcDonald and White 1993). For example, rats may initially move toward a target using hippocampal-dependent knowledge of spatial cues but eventually shift to a more automatic, dorsal striatum–based strategy of performing a fixed sequence of movements (Packard and McGaugh 1996xInactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Packard, M.G. and McGaugh, J.L. Neurobiol. Learn. Mem. 1996; 65: 65–72

Crossref | PubMed | Scopus (656)See all ReferencesPackard and McGaugh 1996). Extended training can also cause performance of a task to no longer be contingent on a desirable outcome (devaluation insensitivity; Balleine and Dickinson 1998xGoal-directed instrumental action (contingency and incentive learning and their cortical substrates) . Balleine, B.W. and Dickinson, A. Neuropharmacology. 1998; 37: 407–419

Crossref | PubMed | Scopus (436)See all ReferencesBalleine and Dickinson 1998), consistent with a shift from evaluative decision making to an automatized stimulus–response habit. Similarly, many different factors, including learning about the motivational significance of drug cues, explicit memories of euphoria, and social pressures, may be responsible for early phases of human drug use. Different drugs may differentially activate these multiple learning processes—for example, nicotine does not provoke substantial euphoria yet is highly addictive, with very high relapse rates (O'Brien and McLellan 1996xMyths about the treatment of addiction. O'Brien, C.P. and McLellan, A.T. Lancet. 1996; 347: 237–240

Abstract | PubMed | Scopus (297)See all ReferencesO'Brien and McLellan 1996). Just as in normal learning, with prolonged drug use the relative roles of distinct neural memory circuits may change (White 1996xAddictive drugs as reinforcers (multiple partial actions on memory systems) . White, N.M. Addiction. 1996; 91: 921–965

Crossref | PubMed | Scopus (221)See all ReferencesWhite 1996), with the increasing automatization of drug-taking behavior being critical for addiction (Tiffany 1990xA cognitive model of drug urges and drug-use behavior (role of automatic and nonautomatic processes) . Tiffany, S.T. Psychol. Rev. 1990; 97: 147–168

Crossref | PubMedSee all ReferencesTiffany 1990). One hypothetical scheme is shown in Table 2Table 2.

We have argued that the most intractable aspects of addiction may result from the inappropriate engagement of molecular mechanisms of long-term memory. In this view, addiction is very different to a brain lesion or a neurodegenerative disease, in that it involves learning specific patterns of information. Through a drug-induced excess of structural synaptic plasticity, certain behavioral “rules” have become strengthened to an unusual degree. Brain circuits involving both dorsal and ventral parts of striatum are likely to be involved in drug self-administration. The likely importance of the ventral striatum in the acquisition of drug-taking behavior should not deter investigations into the role of the dorsal striatum in the transition to addiction.

Drug-associated cues and contexts activate a narrow repertoire of drug-taking behaviors in the fully addicted person. These behaviors can often be suppressed, at least for a time, by “top-down” control mechanisms that are likely to require the prefrontal cortex. Given the deeply ingrained nature of the drug-related behaviors, however, it is not surprising that without effort and vigilance, relapses occur. Clinically, a delicate balance has to be reached. While encouraging addicts to play an active, responsible role in regaining control of their drug intake, at the same time a relapse must not be allowed to signify a catastrophic failure of the treatment (O'Brien and McLellan 1996xMyths about the treatment of addiction. O'Brien, C.P. and McLellan, A.T. Lancet. 1996; 347: 237–240

Abstract | PubMed | Scopus (297)See all ReferencesO'Brien and McLellan 1996).

Most molecular biological accounts of addiction have not emphasized associative learning mechanisms, instead attempting to find a molecular signature of addiction in persistent neurochemical changes (129xDrug abuse (hedonic homeostatic dysregulation) . Koob, G.F. and Le Moal, M. Science. 1997; 278: 52–58

Crossref | PubMed | Scopus (1239)See all References, 131xNeuroscience of addiction. Koob, G.F., Sanna, P.P., and Bloom, F.E. Neuron. 1998; 21: 467–476

Abstract | Full Text | Full Text PDF | PubMed | Scopus (624)See all References). We suggest that the role of transient changes in gene expression, leading to behavioral changes through persistent synaptic rearrangements, deserves greater attention. The current intense investigation of the molecular mechanisms of memory is yielding results that can usefully be applied to the understanding of addiction.