1 Barbeau, A. Drugs affecting movement disorders. Ann. Rev. Pharmacol. 14, 91–113 (1974).

2 Yokel, R. A. & Wise, R. A. Increased lever pressing for amphetamine after pimozide in rats: implications for a dopamine theory of reward. Science 187, 547–549 (1975).

3 Fouriezos, G. & Wise, R. A. Pimozide-induced extinction of intracranial self-stimulation: response patterns rule out motor or performance deficits. Brain Res. 103, 377–380 (1976).

4 Fouriezos, G., Hansson, P. & Wise, R. A. Neuroleptic-induced attenuation of brain stimulation reward in rats. J. Comp. Physiol. Psychol. 92, 661–671 (1978).

5 Wise, R. A., Spindler, J., deWit, H. & Gerber, G. J. Neuroleptic-induced 'anhedonia' in rats: pimozide blocks reward quality of food. Science 201, 262–264 (1978).

6 Gerber, G. J., Sing, J. & Wise, R. A. Pimozide attenuates lever pressing for water reinforcement in rats. Pharmacol. Biochem. Behav. 14, 201–205 (1981).

7 Ettenberg, A. & Camp, C. H. Haloperidol induces a partial reinforcement extinction effect in rats: implications for a dopamine involvement in food reward. Pharmacol. Biochem. Behav. 25, 813–821 (1986).

8 Ettenberg, A. & Camp, C. H. A partial reinforcement extinction effect in water-reinforced rats intermittently treated with haloperidol. Pharmacol. Biochem. Behav. 25, 1231–1235 (1986).

9 McFarland, K. & Ettenberg, A. Haloperidol differentially affects reinforcement and motivational processes in rats running an alley for intravenous heroin. Psychopharmacology 122, 346–350 (1995). A particularly clear demonstration of how neuroleptics impair reinforcement before they impair motivation.

10 McFarland, K. & Ettenberg, A. Haloperidol does not affect motivational processes in an operant runway model of food-seeking behavior. Behav. Neurosci. 112, 630–635 (1998).

11 Franklin, K. B. J. Catecholamines and self-stimulation: reward and performance effects dissociated. Pharmacol. Biochem. Behav. 9, 813–820 (1978).

12 Wise, R. A. Neuroleptics and operant behavior: the anhedonia hypothesis. Behav. Brain Sci. 5, 39–87 (1982).

13 McFarland, K. & Ettenberg, A. Haloperidol does not attenuate conditioned place preferences or locomotor activation produced by food- or heroin-predictive discriminative cues. Pharmacol. Biochem. Behav. 62, 631–641 (1999).

14 Wise, R. A. & Raptis, L. Effects of naloxone and pimozide on initiation and maintenance measures of free feeding. Brain Res. 368, 62–68 (1986). A particularly clear demonstration that neuroleptics attenuate the ability of food to maintain eating long before they attenuate the animal's motivation to feed.

15 Mogenson, G. J., Jones, D. L. & Yim, C. Y. From motivation to action: functional interface between the limbic system and the motor system. Progr. Neurobiol. 14, 69–97 (1980). This classic paper, more than any other, identified nucleus accumbens dopamine with motivational function.

16 Wise, R. A. & Rompré, P. -P. Brain dopamine and reward. Ann. Rev. Psychol. 40, 191–225 (1989).

17 Di Chiara, G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav. Brain Res. 137, 75–114 (2002).

18 Ungerstedt, U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. (Suppl.) 367, 95–122 (1971).

19 Smith, G. P., Strohmayer, A. J. & Reis, D. J. Effect of lateral hypothalamic injections of 6-hydroxydopamine on food and water intake in rats. Nature New Biol. 235, 27–29 (1972).

20 Ervin, G. N., Fink, J. S., Young, R. C. & Smith, G. P. Different behavioral responses to L-DOPA after anterolateral or posterolateral hypothalamic injections of 6-hydroxydopamine. Brain Res. 132, 507–520 (1977).

21 Smith, G. P. The arousal function of central catecholamine neurons. Ann. NY Acad. Sci. 270, 45–56 (1976).

22 Schneirla, T. C. in Nebraska Symposium on Motivation (ed. Jones, M. R.) 1–42 (Univ. Nebraska Press, Lincoln, 1959).

23 Liebman, J. M. & Butcher, L. L. Comparative involvement of dopamine and noradrenaline in rate-free self-stimulation in substantia nigra, lateral hypothalamus, and mesencephalic central gray. Naunyn-Schmiedeberg's Arch. Pharmacol. 284, 167–194 (1974).

24 Franklin, K. B. J. & McCoy, S. N. Pimozide-induced extinction in rats: stimulus control of responding rules out motor deficit. Pharmacol. Biochem. Behav. 11, 71–75 (1979). A nice demonstration of sensory control of responding under neuroleptic treatment. This study refutes the notion that neuroleptic-induced response deficits are the result of motor impairment or vulnerability to fatigue.

25 Gallistel, C. R., Boytim, M., Gomita, Y. & Klebanoff, L. Does pimozide block the reinforcing effect of brain stimulation? Pharmacol. Biochem. Behav. 17, 769–781 (1982).

26 de Wit, H. & Wise, R. A. Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can. J. Psychol. 31, 195–203 (1977).

27 Wise, R. A. & Schwartz, H. V. Pimozide attenuates acquisition of lever pressing for food in rats. Pharmacol. Biochem. Behav. 15, 655–656 (1981).

28 Dickinson, A., Smith, J. & Mirenowicz, J. Dissociation of Pavlovian and instrumental incentive learning under dopamine antagonists. Behav. Neurosci. 114, 468–483 (2000).

29 Lippa, A. S., Antelman, S. M., Fisher, A. E. & Canfield, D. R. Neurochemical mediation of reward: a significant role for dopamine. Pharmacol. Biochem. Behav. 1, 23–28 (1973).

30 Roberts, D. C. S., Corcoran, M. E. & Fibiger, H. C. On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol. Biochem. Behav. 6, 615–620 (1977).

31 Koob, G. F., Fray, P. J. & Iversen, S. D. Self-stimulation at the lateral hypothalamus and locus coeruleus after specific unilateral lesions of the dopamine system. Brain Res. 146, 123–140 (1978).

32 Roberts, D. C. S., Koob, G. F., Klonoff, P. & Fibiger, H. C. Extinction and recovery of cocaine self-administration following 6-OHDA lesions of the nucleus accumbens. Pharmacol. Biochem. Behav. 12, 781–787 (1980).

33 Roberts, D. C. S. & Koob, G. Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats. Pharmacol. Biochem. Behav. 17, 901–904 (1982).

34 Fibiger, H. C. Drugs and reinforcement mechanisms: a critical review of the catecholamine theory. Ann. Rev. Pharmacol. Toxicol. 18, 37–56 (1978).

35 Wise, R. A. Catecholamine theories of reward: a critical review. Brain Res. 152, 215–247 (1978).

36 Wise, R. A. in The Neuropharmacological Basis of Reward (eds Liebman, J. M. & Cooper, S. J.) 377–424 (Oxford Univ. Press, Oxford, 1989).

37 Wise, R. A., Spindler, J. & Legault, L. Major attenuation of food reward with performance-sparing doses of pimozide in the rat. Can. J. Psychol. 32, 77–85 (1978).

38 Smith, G. P. in Progress in Psychobiology and Physiological Psychology (eds Morrison, A. & Fluharty, S.) 83–144 (Academic, New York, 1995).

39 Mason, S. T., Beninger, R. J., Fibiger, H. C. & Phillips, A. G. Pimozide-induced suppression of responding: evidence against a block of food reward. Pharmacol. Biochem. Behav. 12, 917–923 (1980).

40 Koob, G. F. The dopamine anhedonia hypothesis: a pharmacological phrenology. Behav. Brain Sci. 5, 63–64 (1982).

41 Ettenberg, A., Koob, G. F. & Bloom, F. E. Response artifact in the measurement of neuroleptic-induced anhedonia. Science 213, 357–359 (1981).

42 Salamone, J. D., Cousins, M. S. & Snyder, B. J. Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci. Biobehav. Rev. 21, 341–359 (1997).

43 Beninger, R. J. The role of dopamine in locomotor activity and learning. Brain Res. Rev. 6, 173–196.

44 Spyraki, C., Fibiger, H. C. & Phillips, A. G. Attenuation by haloperidol of place preference conditioning using food reinforcement. Psychopharmacology 77, 379–382 (1982).

45 Bozarth, M. A. & Wise, R. A. Heroin reward is dependent on a dopaminergic substrate. Life Sci. 29, 1881–1886 (1981).

46 Spyraki, C., Fibiger, H. C. & Phillips, A. G. Dopaminergic substrates of amphetamine-induced place preference conditioning. Brain Res. 253, 185–193 (1982).

47 Spyraki, C., Fibiger, H. C. & Phillips, A. G. Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system. Psychopharmacology 79, 278–283 (1983).

48 Spyraki, C., Nomikos, G. G. & Varonos, D. D. Intravenous cocaine-induced place preference: attenuation by haloperidol. Behav. Brain. Res. 26, 57–62 (1987).

49 Carlezon, W. A. Jr & Wise, R. A. Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J. Neurosci. 16, 3112–3122 (1996).

50 Brown, L. L. Sensory and cognitive functions of the basal ganglia. Curr. Opin. Neurobiol. 7, 157–163 (1997).

51 Jenner, P. The MPTP-treated primate as a model of motor complications in PD: primate model of motor complications. Neurology 61, (Suppl. 3) S4–11 (2003).

52 Bindra, D. Neuropsychological interpretation of the effects of drive and incentive-motivation on general activity and instrumental behavior. Psychol. Rev. 75, 1–22 (1968).

53 Wetzel, M. C. Self-stimulation aftereffects and runway performance in the rat. J. Comp. Physiol. Psychol. 56, 673–678 (1963).

54 Gallistel, C. R., Stellar, J. R. & Bubis, E. Parametric analysis of brain stimulation reward in the rat: I. The transient process and the memory-containing process. J. Comp. Physiol. Psychol. 87, 848–859 (1974). This classic paper distinguishes clearly between the priming and reinforcing functions of brain stimulation reward. The first decays in seconds, whereas the second is effective for weeks.

55 Pickens, R. & Harris, W. C. Self-administration of D-amphetamine by rats. Psychopharmacologia 12, 158–163 (1968).

56 Esposito, R. U., Faulkner, W. & Kornetsky, C. Specific modulation of brain stimulation reward by haloperidol. Pharmacol. Biochem. Behav. 10, 937–940 (1979). Although it is couched in terms of reinforcement, this study measures the priming effects of free brain stimulation on the latency to lever-press for more.

57 Wasserman, E. M., Gomita, Y. & Gallistel, C. R. Pimozide blocks reinforcement but not priming from MFB stimulation in the rat. Pharmacol. Biochem. Behav. 17, 783–787 (1982). This study shows that the priming effect of stimulation undergoes an extinction-like decline under neuroleptic treatment, indicating that even the rapidly decaying priming effect is partially conditioned.

58 Shaham, Y., Adamson, L. K., Grocki, S. & Corrigall, W. A. Reinstatement and spontaneous recovery of nicotine seeking in rats. Psychopharmacology 130, 396–403 (1997).

59 de Wit, H. & Stewart, J. Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75, 134–143 (1981).

60 Wise, R. A., Murray, A. & Bozarth, M. A. Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever-pressing in rats. Psychopharmacology 100, 355–360 (1990).

61 Phillips, P. E., Stuber, G. D., Heien, M. L., Wightman, R. M. & Carelli, R. M. Subsecond dopamine release promotes cocaine seeking. Nature 422, 614–618 (2003).

62 Cornish, J. L. & Kalivas, P. W. Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J. Neurosci. 20, RC89 (2000).

63 Roitman, M. F., Stuber, G. D., Phillips, P. E., Wightman, R. M. & Carelli, R. M. Dopamine operates as a subsecond modulator of food seeking. J. Neurosci. 24, 1265–1271 (2004).

64 Wyvell, C. L. & Berridge, K. C. Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward 'wanting' without enhanced 'liking' or response reinforcement. J. Neurosci. 20, 8122–8130 (2000).

65 Crespi, L. P. Quantitative variation of incentive and performance in the white rat. Am. J. Psychol. 55, 467–517 (1942).

66 Stewart, J., de Wit, H. & Eikelboom, R. Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol. Rev. 91, 251–268 (1984).

67 Mendelson, J. The role of hunger in the T-maze learning for food by rats. J. Comp. Physiol. Psychol. 62, 341–349 (1966).

68 Morgan, M. J. Resistance to satiation. Anim. Behav. 22, 449–466 (1974). References 67 and 68 show that response initiation depends more on the animal's habit strength based on recent reinforcement history than on the current hunger level of the animal. The parallel between the role of hunger and the role of dopamine in response initiation in well-trained animals is central to the suggestions of the current review.

69 Wise, R. A. & Colle, L. M. Pimozide attenuates free feeding: best scores analysis reveals a motivational deficit. Psychopharmacology 84, 446–451 (1984).

70 Koechling, U., Colle, L. M. & Wise, R. A. Effects of SCH 23390 on latency and speed measures of deprivation-induced feeding. Psychobiology 16, 207–212 (1988).

71 Ljungberg, T., Apicella, P. & Schultz, W. Responses of monkey dopamine neurons during learning of behavioral reactions. J. Neurophysiol. 67, 145–163 (1992).

72 Schultz, W., Apicella, P. & Ljungberg, T. Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. J. Neurosci. 13, 900–913 (1993).

73 Hernandez, L. & Hoebel, B. G. Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measured by microdialysis. Life Sci. 42, 1705–1712 (1988).

74 Wise, R. A., Leone, P., Rivest, R. & Leeb, K. Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration. Synapse 21, 140–148 (1995).

75 Wise, R. A. et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology 120, 10–20 (1995).

76 Ranaldi, R., Pocock, D., Zereik, R. & Wise, R. A. Dopamine fluctuations in the nucleus accumbens during maintenance, extinction, and reinstatement of intravenous D-amphetamine self-administration. J. Neurosci. 19, 4102–4109 (1999).

77 Taylor, J. R. & Robbins, T. W. Enhanced behavioural control by conditioned reinforcers produced by intracerebral injections of D-amphetamine in the rat. Psychopharmacology 84, 405–412 (1984).

78 Taylor, J. R. & Robbins, T. W. 6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine. Psychopharmacology 90, 390–397 (1986).

79 Laruelle, M. et al. SPECT imaging of striatal dopamine release after amphetamine challenge. J. Nuc. Med. 36, 1182–1190 (1995).

80 Volkow, N. D. et al. Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J. Pharmacol. Exp. Ther. 291, 409–415 (1999).

81 Drevets, W. C. et al. Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol. Psychiatry 49, 81–96 (2001).

82 Jönsson, L., Ånggard, E. & Gunne, L. Blockade of intravenous amphetamine euphoria in man. Clin. Pharmacol. Ther. 12, 889–896 (1971).

83 Gunne, L. M., Ånggard, E. & Jönsson, L. E. Clinical trials with amphetamine-blocking drugs. Psychiatr. Neurol. Neurochir. 75, 225–226 (1972).

84 Brauer, L. H. & de Wit, H. High dose pimozide does not block amphetamine-induced euphoria in normal volunteers. Pharmacol. Biochem. Behav. 56, 265–272 (1997).

85 Martinez, D. et al. Cocaine dependence and D2 receptor availability in functional subdivisions of the striatum: relationship with cocaine-seeking behavior. Neuropsychopharmacology (in the press).

86 Kelleher, R. T. & Morse, W. H. Schedules using noxious stimuli. 3. Responding maintained with response produced electric shocks. J. Exper. Anal. Behav. 11, 819–838 (1968).

87 Horrocks, J. & House, A. Self-poisoning and self-injury in adults. Clin. Med. 2, 509–512 (2002).

88 Foltin, R. W. & Fischman, M. W. Smoked and intravenous cocaine in humans: acute tolerance, cardiovascular and subjective effects. J. Pharmacol. Exp. Ther. 257, 247–261 (1991).

89 Lamb, R. J. et al. The reinforcing and subjective effects of morphine in post-addicts: a dose-response study. J. Pharmacol. Exp. Ther. 259, 1165–1173 (1991).

90 Russell, M. A. Subjective and behavioural effects of nicotine in humans: some sources of individual variation. Prog. Brain Res. 79, 289–302 (1989).

91 Johanson, C. E. in Contemporary Research in Behavioral Pharmacology (eds Blackman, D. E. & Sanger, D. J.) 325–390 (Plenum, New York, 1978).

92 Berridge, K. C. Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns. Neurosci. Biobehav. Rev. 24, 173–198 (2000).

93 Berridge, K. D., Venier, I. L. & Robinson, T. E. Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function. Behav. Neurosci. 103, 36–45 (1989).

94 Pecina, S., Berridge, K. C. & Parker, L. A. Pimozide does not shift palatability: separation of anhedonia from sensorimotor suppression by taste reactivity. Pharmacol. Biochem. Behav. 58, 801–811 (1997).

95 Leeb, K., Parker, L. & Eikelboom, R. Effects of pimozide on the hedonic properties of sucrose: analysis by the taste reactivity test. Pharmacol. Biochem. Behav. 39, 895–901 (1991).

96 Grill, H. J. & Norgren, R. The taste reactivity test. II. Mimetic responses to gustatory stimuli in chronic thalamic and chronic decerebrate rats. Brain Res. 143, 281–297 (1978).

97 Steiner, J. E. The gustofacial response: observation on normal and anencephalic newborn infants. Symp. Oral Sens. Percept. 4, 254–278 (1973).

98 Berridge, K. C., Flynn, F. W., Schulkin, J. & Grill, H. J. Sodium depletion enhances salt palatability in rats. Behav. Neurosci. 98, 652–660 (1984).

99 Berridge, K. C. & Robinson, T. E. The mind of an addicted brain: neural sensitization of wanting and liking. Curr. Direct. Psychol. Sci. 4, 71–76 (1995).

100 Wise, R. A. Sensorimotor modulation and the variable action pattern (VAP): toward a noncircular definition of drive and motivation. Psychobiology 15, 7–20 (1987).

101 Ettenberg, A., Pettit, H. O., Bloom, F. E. & Koob, G. F. Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology 78, 204–209 (1982).

102 Salamone, J. D., Cousins, M. S. & Bucher, S. Anhedonia or anergia? Effects of haloperidol and nucleus accumbens dopamine depletion on instrumental response selection in a T-maze cost/benefit procedure. Behav. Brain Res. 65, 221–229 (1994).

103 Neill, D. B. & Justice, J. B. J. in The Neurobiology of the Nucleus Accumbens (eds Chronister, R. B. & DeFrance, J. F.) 515–528 (Haer Institute, New Brunswick, 1981).

104 Salamone, J. D. & Correa, M. Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav. Brain Res. 137, 3–25 (2002).

105 Aberman, J. E. & Salamone, J. D. Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement. Neuroscience 92, 545–552 (1999).

106 Lyness, W. H., Friedle, N. M. & Moore, K. E. Destruction of dopaminergic nerve terminals in nucleus accumbens: effect on D-amphetamine self-administration. Pharmacol. Biochem. Behav. 11, 553–556 (1979).

107 Hanlon, E. C., Baldo, B. A., Sadeghian, K. & Kelley, A. E. Increases in food intake or food-seeking behavior induced by GABAergic, opioid, or dopaminergic stimulation of the nucleus accumbens: is it hunger? Psychopharmacology 172, 241–247 (2004).

108 Bakshi, V. P. & Kelley, A. E. Striatal regulation of morphine-induced hyperphagia: an anatomical mapping study. Psychopharmacology 111, 207–214 (1993).

109 Olds, M. E. Reinforcing effects of morphine in the nucleus accumbens. Brain Res. 237, 429–440 (1982).

110 Olds, M. E. & Williams, K. N. Self-administration of D-ala2-met-enkephalinamide at hypothalamic self-stimulation sites. Brain Res. 194, 155–170 (1980).

111 Goeders, N. E., Lane, J. D. & Smith, J. E. Self-administration of methionine enkephalin into the nucleus accumbens. Pharmacol. Biochem. Behav. 20, 451–455 (1984).

112 Hoebel, B. G. et al. Self-injection of amphetamine directly into the brain. Psychopharmacology 81, 158–163 (1983).

113 Phillips, G. D., Robbins, T. W. & Everitt, B. J. Bilateral intra-accumbens self-administration of D-amphetamine: antagonism with intra-accumbens SCH-23390 and sulpiride. Psychopharmacology 114, 477–485 (1994).

114 Carlezon, W. A. Jr, Devine, D. P. & Wise, R. A. Habit-forming actions of nomifensine in nucleus accumbens. Psychopharmacology (Berl.) 122, 194–197 (1995).

115 Johnson, A. K. & Epstein, A. N. The cerebral ventricles as the avenue for the dipsogenic action of intracranial angiotensin. Brain Res. 86, 399–418 (1975). The potential for migration of centrally administered drugs to and through the ventricular system is nicely illustrated in this classic paper.

116 Bozarth, M. A. & Wise, R. A. Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sci. 28, 551–555 (1981).

117 Carlezon, W. A. Jr & Wise, R. A. Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate lateral hypothalamic brain stimulation reward. Psychopharmacology 128, 413–420 (1996).

118 Goeders, N. E. & Smith, J. E. Cortical dopaminergic involvement in cocaine reinforcement. Science 221, 773–775 (1983).

119 Ikemoto, S. Involvement of the olfactory tubercle in cocaine reward: intracranial self-administration studies. J. Neurosci. 23, 9305–9511 (2003).

120 Wise, R. A. & Bozarth, M. A. A psychomotor stimulant theory of addiction. Psychol. Rev. 94, 469–492 (1987).

121 Di Chiara, G. & Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl Acad. Sci. USA 85, 5274–5278 (1988).

122 Bechara, A., Harrington, F., Nader, K. & van der Kooy, D. Neurobiology of motivation: double dissociation of two motivational mechanisms mediating opiate reward in drug-naive versus drug-dependent rats. Behav. Neurosci. 106, 798–807 (1992).

123 Laviolette, S. R. & van der Kooy, D. Blockade of mesolimbic dopamine transmission dramatically increases sensitivity to the rewarding effects of nicotine in the ventral tegmental area. Mol. Psychiatry 8, 50–59 (2003).

124 Wise, R. A. The neurobiology of craving: implications for the understanding and treatment of addiction. J. Abnorm. Psychol. 97, 118–132 (1988).

125 Heikkila, R. E., Orlansky, H. & Cohen, G. Studies on the distinction between uptake inhibition and release of (3H)dopamine in rat brain tissue slices. Biochem. Pharmacol. 24, 847–852 (1975).

126 Ritz, M. C., Lamb, R. J., Goldberg, S. R. & Kuhar, M. J. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237, 1219–1223 (1987).

127 Rocha, B. A. et al. Cocaine self-administration in dopamine-transporter knockout mice. Nature Neurosci. 1, 132–137 (1998).

128 Sora, I. et al. Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc. Natl Acad. Sci. USA 95, 699–704 (1998).

129 Morón, J. A., Brockington, A., Wise, R. A., Rocha, B. A. & Hope, B. T. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J. Neurosci. 22, 389–395 (2002).

130 Carboni, E. et al. Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene. J. Neurosci. 21, 1–4 (2001).

131 Sora, I. et al. Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc. Natl Acad. Sci. USA 98, 5300–5305 (2001).

132 Loh, E. A. & Roberts, D. C. S. Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology 101, 262–266 (1990).

133 Lyness, W. H., Friedle, N. M. & Moore, K. E. Increased self-administration of D-amphetamine after destruction of 5-hydroxytryptaminergic nerves. Pharmacol. Biochem. Behav. 12, 937–941 (1981).

134 Berridge, K. C. & Robinson, T. E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Rev. 28, 309–369 (1998).

135 Berridge, K. C. & Robinson, T. E. Parsing reward. Trends Neurosci. 26, 507–513 (2003).

136 Robinson, T. E. & Berridge, K. C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Reviews 18, 247–292 (1993).

137 Schultz, W. & Dickinson, A. Neuronal coding of prediction errors. Ann. Rev. Neurosci. 23, 473–500 (2000).

138 Contreras-Vidal, J. L. & Schultz, W. A predictive reinforcement model of dopamine neurons for learning approach behavior. J. Comput. Neurosci. 6, 191–214 (1999).

139 Romo, R. & Schultz, W. Dopamine neurons of the monkey midbrain: contingencies of responses to active touch during self-initiated arm movements. J. Neurophysiol. 63, 592–606 (1990).

140 Schultz, W., Apicella, P., Scarnati, E. & Ljungberg, T. Neuronal activity in monkey ventral striatum related to the expectation of reward. J. Neurosci. 12, 4595–4610 (1992).

141 Wise, R. A. Brain reward circuitry: insights from unsensed incentives. Neuron 36, 229–240 (2002).

142 Robbins, T. W. The acquisition of responding with conditioned reinforcement: effects of pipradrol, methylphenidate, D-amphetamine and nomifensine. Psychopharmacology 58, 79–87 (1978).

143 Rozin, P. & Kalat, J. W. Specific hungers and poison avoidance as adaptive specializations of learning. Psychol. Rev. 78, 459–486 (1971).

144 Le Magnen, J. Effets des administrations post-prandiales de glucose sur l'etablissement des appétits. C. R. Seances Soc. Biol. Fil. 158, 212–215 (1959).

145 Myers, K. P. & Sclafani, A. Conditioned enhancement of flavor evaluation reinforced by intragastric glucose. II. Taste reactivity analysis. Physiol. Behav. 74, 495–505 (2001).

146 Messier, C. & White, N. M. Contingent and non-contingent actions of sucrose and saccharin reinforcers: effects on taste preference and memory. Physiol. Behav. 32, 195–203 (1984).

147 Di Ciano, P. & Everitt, B. J. Differential control over drug-seeking behavior by drug-associated conditioned reinforcers and discriminative stimuli predictive of drug availability. Behav. Neurosci. 117, 952–960 (2003).

148 Changizi, M. A., McGehee, R. M. & Hall, W. G. Evidence that appetitive responses for dehydration and food-deprivation are learned. Physiol. Behav. 75, 295–304 (2002).

149 Hall, W. G., Cramer, C. P. & Blass, E. M. Developmental changes in suckling of rat pups. Nature 258, 318–320 (1975).

150 Johanson, I. B. & Hall, W. G. Appetitive learning in 1-day-old rat pups. Science 205, 419–421 (1979).

151 Balleine, B. Instrumental performance following a shift in primary motivation depends on incentive learning. J. Exp. Psychol. Anim. Behav. Process. 18, 236–250 (1992).

152 Landauer, T. K. Reinforcement as consolidation. Psychol. Rev. 76, 82–96 (1969).

153 Pfaff, D. Parsimonious biological models of memory and reinforcement. Psychol. Rev. 76, 70–81 (1969).

154 Huston, J. P., Mondadori, C. & Waser, P. G. Facilitation of learning by reward of post-trial memory processes. Experietia 30, 1038–1040 (1974).

155 Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

156 Frey, U., Schroeder, H. & Matthies, H. Dopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices. Brain Res. 522, 69–75 (1990).

157 Frey, U., Matthies, H., Reymann, K. G. & Matthies, H. The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro. Neurosci. Lett. 129, 111–114 (1991).

158 Li, S., Cullen, W. K., Anwyl, R. & Rowan, M. J. Dopamine-dependent facilitation of LTP induction in hippocampal CA1 by exposure to spatial novelty. Nature Neurosci. 6, 526–531 (2003).

159 Swanson-Park, J. L. et al. A double dissociation within the hippocampus of dopamine D1/D5 receptor and β-adrenergic receptor contributions to the persistence of long-term potentiation. Neuroscience 92, 485–497 (1999).

160 Otmakhova, N. A. & Lisman, J. E. D1/D5 dopamine receptors inhibit depotentiation at CA1 synapses via cAMP-dependent mechanism. J. Neurosci. 18, 1270–1279 (1998).

161 Chen, Z. et al. Roles of dopamine receptors in long-term depression: enhancement via D1 receptors and inhibition via D2 receptors. Recept. Channels 4, 1–8 (1996).

162 Calabresi, P., Maj, R., Pisani, A., Mercuri, N. B. & Bernardi, G. Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J. Neurosci. 12, 4224–4233 (1992).

163 Centonze, D., Picconi, B., Gubellini, P., Bernardi, G. & Calabresi, P. Dopaminergic control of synaptic plasticity in the dorsal striatum. Eur. J. Neurosci. 13, 1071–1077 (2001).

164 Bissiere, S., Humeau, Y. & Luthi, A. Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nature Neurosci. 6, 587–592 (2003).

165 Huang, Y. Y., Simpson, E., Kellendonk, C. & Kandel, E. R. Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc. Natl Acad. Sci. USA 101, 3236–3241 (2004).

166 Otani, S., Daniel, H., Roisin, M. P. & Crepel, F. Dopaminergic modulation of long-term synaptic plasticity in rat prefrontal neurons. Cereb. Cortex 13, 1251–1256 (2003).

167 Law-Tho, D., Desce, J. M. & Crepel, F. Dopamine favours the emergence of long-term depression versus long-term potentiation in slices of rat prefrontal cortex. Neurosci. Lett. 188, 125–128 (1995).

168 Pennartz, C. M., Ameerun, R. F., Groenewegen, H. J. & Lopes da Silva, F. H. Synaptic plasticity in an in vitro slice preparation of the rat nucleus accumbens. Eur. J. Neurosci. 5, 107–117 (1993).

169 Kombian, S. B. & Malenka, R. C. Simultaneous LTP of non-NMDA- and LTD of NMDA-receptor-mediated responses in the nucleus accumbens. Nature 368, 242–246 (1994).

170 Overton, P. G., Richards, C. D., Berry, M. S. & Clark, D. Long-term potentiation at excitatory amino acid synapses on midbrain dopamine neurons. Neuroreport 10, 221–226 (1999).

171 Bonci, A. & Malenka, R. C. Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J. Neurosci. 19, 3723–3730 (1999).

172 Thomas, M. J., Malenka, R. C. & Bonci, A. Modulation of long-term depression by dopamine in the mesolimbic system. J. Neurosci. 20, 5581–5586 (2000).

173 Saal, D., Dong, Y., Bonci, A. & Malenka, R. C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37, 577–582 (2003).

174 White, N. M. & Viaud, M. Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats. Behav. Neural Biol. 55, 255–269 (1991). This paper shows that dopamine enhances memory consolidation involving different sensory modalities in different portions of the striatum.

175 Packard, M. G., Cahill, L. & McGaugh, J. L. Amygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes. Proc. Natl Acad. Sci. USA 91, 8477–8481 (1994).

176 Hitchcott, P. K. & Phillips, G. D. Double dissociation of the behavioural effects of R(+) 7-OH-DPAT infusions in the central and basolateral amygdala nuclei upon Pavlovian and instrumental conditioned appetitive behaviours. Psychopharmacology 140, 458–469 (1998).

177 Wise, R. A. Drug-activation of brain reward pathways. Drug Alcohol Depend. 51, 13–22 (1998).

178 Sesack, S. R., Carr, D. B., Omelchenko, N. & Pinto, A. Anatomical substrates for glutamate-dopamine interactions: evidence for specificity of connections and extrasynaptic actions. Ann. NY Acad. Sci. 1003, 36–52 (2003).

179 You, Z. -B., Tzschentke, T. M., Brodin, E. & Wise, R. A. Electrical stimulation of the prefrontal cortex increases cholecystokinin, glutamate, and dopamine release in the nucleus accumbens: an in vivo microdialysis study in freely moving rats. J. Neurosci. 18, 6492–6500 (1998).

180 Goeders, N. E. & Smith, J. E. Intracranial cocaine self-administration into the medial prefrontal cortex increases dopamine turnover in the nucleus accumbens. J. Pharmacol. Exp. Ther. 265, 592–600 (1993).

181 Williams, G. V. & Goldman-Rakic, P. S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376, 572–575 (1995).

182 McFarland, K. & Kalivas, P. W. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 21, 8655–8663 (2001).

183 McFarland, K., Lapish, C. C. & Kalivas, P. W. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 23, 3531–3537 (2003).

184 Capriles, N., Rodaros, D., Sorge, R. E. & Stewart, J. A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology 168, 66–74 (2003).

185 Sanchez, C. J., Bailie, T. M., Wu, W. R., Li, N. & Sorg, B. A. Manipulation of dopamine d1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior. Neuroscience 119, 497–505 (2003).

186 Cador, M., Robbins, T. W. & Everitt, B. J. Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum. Neuroscience 30, 77–86 (1989).

187 Whitelaw, R. B., Markou, A., Robbins, T. W. & Everitt, B. J. Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology 127, 213–224 (1996).

188 Hall, J., Parkinson, J. A., Connor, T. M., Dickinson, A. & Everitt, B. J. Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour. Eur. J. Neurosci. 13, 1984–1992 (2001).

189 Pears, A., Parkinson, J. A., Hopewell, L., Everitt, B. J. & Roberts, A. C. Lesions of the orbitofrontal but not medial prefrontal cortex disrupt conditioned reinforcement in primates. J. Neurosci. 23, 11189–11201 (2003).

190 Hutcheson, D. M. & Everitt, B. J. The effects of selective orbitofrontal cortex lesions on the acquisition and performance of cue-controlled cocaine seeking in rats. Ann. NY Acad. Sci. 1003, 410–411 (2003).

191 Schoenbaum, G., Setlow, B., Saddoris, M. P. & Gallagher, M. Encoding predicted outcome and acquired value in orbitofrontal cortex during cue sampling depends upon input from basolateral amygdala. Neuron 39, 855–867 (2003).

192 Prado-Alcala, R. & Wise, R. A. Brain stimulation reward and dopamine terminal fields. I. Caudate-putamen, nucleus accumbens and amygdala. Brain Res. 297, 265–273 (1984).

193 Ursin, R., Ursin, H. & Olds, J. Self-stimulation of hippocampus in rats. J. Comp. Physiol. Psychol. 61, 353–359 (1966).

194 Phillips, A. G., Mora, F. & Rolls, E. T. Intracerebral self-administration of amphetamine by rhesus monkeys. Neurosci. Lett. 24, 81–86 (1981).

195 Stevens, K. E., Shiotsu, G. & Stein, L. Hippocampal μ-receptors mediate opioid reinforcement in the CA3 region. Brain Res. 545, 8–16 (1991).

196 Fallon, J. H. & Moore, R. Y. Catecholamine innervation of the basal forebrain. IV. Topography of the dopamine projection to the basal forebrain and neostriatum. J. Comp. Neurol. 180, 545–580 (1978). This classic paper first characterized the midbrain dopamine system as a single system with topologically graded projections rather than a set of independent, non-overlapping systems. This anatomical perspective is fundamental to the suggestion that dopamine plays similar parts in various of its projection fields.

197 Heimer, L., Zahm, D. S. & Alheid, G. F. in The Rat Nervous System (ed. Paxinos, G.) 579–628 (Academic, New York, 1995).