Dopamine, learning and motivation

Key Points

  • Brain dopamine has been linked to both motor and motivational functions. Several motivational hypotheses have been challenged and found inadequate, but it remains clear that dopamine is vital for the 'stamping-in' of stimulus–reward and response–reward associations.

  • Stimulus–reward associations are, in turn, crucial for the subsequent motivation in a previous-reward situation. Response habits are triggered by environmental stimuli that have been previously associated with reward, and the initiation of such response habits is not dependent on immediate dopamine function. If repeated with dopamine function blocked, however, the old stimulus–reward associations are extinguished and response motivation progressively weakens.

  • While the motivational effectiveness of reward-associated stimuli does not require immediate dopamine function, phasic dopamine elevations can nonetheless amplify stimulus effectiveness. This amplification is thought to be a dopamine function in the nucleus accumbens.

  • The role of dopamine in the stamping-in of reward associations might be much less localized. Dopamine seems to have important roles in the consolidation of memory in various structures — structures that are linked to different kinds of learning or to the learning of different things.

  • A full appreciation of the role of dopamine in motivation must be on the basis of an understanding of not only the role of dopamine in immediate behavioural arousal, but also its role in the learning and memory of learned motivational stimuli.

Abstract

The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.

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Figure 1: Effect of dopamine receptor blockade on lever-pressing for brain stimulation reward.
Figure 2: Effect of dopamine receptor blockade on lever-pressing for food reward.
Figure 3: Effect of dopamine receptor blockade on lever-pressing for brain stimulation reward.
Figure 4: Effect of dopamine receptor blockade on free feeding.
Figure 5: Effect of dopamine receptor blockade during training on the strength of subsequent performance.

References

  1. 1

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

    CAS  Article  Google Scholar 

  2. 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).

    CAS  Article  PubMed  Google Scholar 

  3. 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).

    CAS  Article  PubMed  Google Scholar 

  4. 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).

    CAS  Article  PubMed  Google Scholar 

  5. 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).

    CAS  Article  PubMed  Google Scholar 

  6. 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).

    CAS  Article  PubMed  Google Scholar 

  7. 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).

    CAS  Article  PubMed  Google Scholar 

  8. 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).

    CAS  Article  PubMed  Google Scholar 

  9. 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.

    CAS  Article  PubMed  Google Scholar 

  10. 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).

    CAS  Article  PubMed  Google Scholar 

  11. 11

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

    CAS  Article  PubMed  Google Scholar 

  12. 12

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

    Article  Google Scholar 

  13. 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).

    CAS  Article  PubMed  Google Scholar 

  14. 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.

    CAS  Article  PubMed  Google Scholar 

  15. 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.

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  PubMed  Google Scholar 

  18. 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).

    CAS  Article  Google Scholar 

  19. 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).

    CAS  Article  PubMed  Google Scholar 

  20. 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).

    CAS  Article  PubMed  Google Scholar 

  21. 21

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

    CAS  Article  PubMed  Google Scholar 

  22. 22

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

    Google Scholar 

  23. 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).

    CAS  Article  Google Scholar 

  24. 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.

    CAS  Article  PubMed  Google Scholar 

  25. 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).

    CAS  Article  PubMed  Google Scholar 

  26. 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).

    CAS  Article  PubMed  Google Scholar 

  27. 27

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

    CAS  Article  PubMed  Google Scholar 

  28. 28

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

    CAS  Article  PubMed  Google Scholar 

  29. 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).

    CAS  Article  PubMed  Google Scholar 

  30. 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).

    CAS  Article  PubMed  Google Scholar 

  31. 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).

    CAS  Article  PubMed  Google Scholar 

  32. 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).

    CAS  Article  PubMed  Google Scholar 

  33. 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).

    CAS  Article  PubMed  Google Scholar 

  34. 34

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

    CAS  Article  Google Scholar 

  35. 35

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

    CAS  Article  PubMed  Google Scholar 

  36. 36

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

    Google Scholar 

  37. 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).

    CAS  Article  PubMed  Google Scholar 

  38. 38

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

    Google Scholar 

  39. 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).

    CAS  Article  PubMed  Google Scholar 

  40. 40

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

    Article  Google Scholar 

  41. 41

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

    CAS  Article  PubMed  Google Scholar 

  42. 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).

    CAS  Article  PubMed  Google Scholar 

  43. 43

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

  44. 44

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

    CAS  Article  PubMed  Google Scholar 

  45. 45

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

    CAS  Article  PubMed  Google Scholar 

  46. 46

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

    CAS  Article  PubMed  Google Scholar 

  47. 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).

    CAS  Article  PubMed  Google Scholar 

  48. 48

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

    CAS  Article  PubMed  Google Scholar 

  49. 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).

    CAS  Article  PubMed  Google Scholar 

  50. 50

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

    CAS  Article  PubMed  Google Scholar 

  51. 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).

    CAS  Article  PubMed  Google Scholar 

  52. 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).

    Article  Google Scholar 

  53. 53

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

    CAS  Article  PubMed  Google Scholar 

  54. 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.

    CAS  Article  PubMed  Google Scholar 

  55. 55

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

    CAS  Article  PubMed  Google Scholar 

  56. 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.

    CAS  Article  PubMed  Google Scholar 

  57. 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.

    CAS  Article  PubMed  Google Scholar 

  58. 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).

    CAS  Article  PubMed  Google Scholar 

  59. 59

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

    CAS  Article  PubMed  Google Scholar 

  60. 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).

    CAS  Article  PubMed  Google Scholar 

  61. 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).

    CAS  Article  PubMed  Google Scholar 

  62. 62

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

    CAS  Article  PubMed  Google Scholar 

  63. 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).

    CAS  Article  PubMed  Google Scholar 

  64. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

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

    Article  Google Scholar 

  66. 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).

    CAS  Article  PubMed  Google Scholar 

  67. 67

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

    Article  Google Scholar 

  68. 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.

    Article  Google Scholar 

  69. 69

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

    CAS  Article  PubMed  Google Scholar 

  70. 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).

    CAS  Google Scholar 

  71. 71

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

    CAS  Article  PubMed  Google Scholar 

  72. 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).

    CAS  Article  PubMed  Google Scholar 

  73. 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).

    CAS  Article  PubMed  Google Scholar 

  74. 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).

    CAS  Article  PubMed  Google Scholar 

  75. 75

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

    CAS  Article  PubMed  Google Scholar 

  76. 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).

    CAS  Article  PubMed  Google Scholar 

  77. 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).

    CAS  Article  PubMed  Google Scholar 

  78. 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).

    CAS  Article  PubMed  Google Scholar 

  79. 79

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

    CAS  Google Scholar 

  80. 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).

    CAS  PubMed  Google Scholar 

  81. 81

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

    CAS  Article  PubMed  Google Scholar 

  82. 82

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

    Article  PubMed  Google Scholar 

  83. 83

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

    CAS  PubMed  Google Scholar 

  84. 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).

    CAS  Article  PubMed  Google Scholar 

  85. 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. 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).

    CAS  Article  Google Scholar 

  87. 87

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

    Article  Google Scholar 

  88. 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).

    CAS  PubMed  Google Scholar 

  89. 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).

    CAS  PubMed  Google Scholar 

  90. 90

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

    CAS  Article  PubMed  Google Scholar 

  91. 91

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

    Google Scholar 

  92. 92

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

    CAS  Article  PubMed  Google Scholar 

  93. 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).

    CAS  Article  PubMed  Google Scholar 

  94. 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).

    CAS  Article  PubMed  Google Scholar 

  95. 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).

    CAS  Article  PubMed  Google Scholar 

  96. 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).

    CAS  Article  PubMed  Google Scholar 

  97. 97

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

    Google Scholar 

  98. 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).

    CAS  Article  PubMed  Google Scholar 

  99. 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).

    Article  Google Scholar 

  100. 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).

    Google Scholar 

  101. 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).

    CAS  Article  PubMed  Google Scholar 

  102. 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).

    CAS  Article  PubMed  Google Scholar 

  103. 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).

    Google Scholar 

  104. 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).

    CAS  Article  PubMed  Google Scholar 

  105. 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).

    CAS  Article  PubMed  Google Scholar 

  106. 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).

    CAS  Article  PubMed  Google Scholar 

  107. 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).

    CAS  Article  PubMed  Google Scholar 

  108. 108

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

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

    CAS  Article  PubMed  Google Scholar 

  110. 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).

    CAS  Article  PubMed  Google Scholar 

  111. 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).

    CAS  Article  PubMed  Google Scholar 

  112. 112

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

    CAS  Article  PubMed  Google Scholar 

  113. 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).

    CAS  Article  PubMed  Google Scholar 

  114. 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).

    CAS  Article  Google Scholar 

  115. 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.

    CAS  Article  PubMed  Google Scholar 

  116. 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).

    CAS  Article  PubMed  Google Scholar 

  117. 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).

    CAS  Article  PubMed  Google Scholar 

  118. 118

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

    CAS  Article  PubMed  Google Scholar 

  119. 119

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

    CAS  Article  PubMed  Google Scholar 

  120. 120

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

    CAS  Article  PubMed  Google Scholar 

  121. 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).

    CAS  Article  PubMed  Google Scholar 

  122. 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).

    CAS  Article  PubMed  Google Scholar 

  123. 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).

    CAS  Article  PubMed  Google Scholar 

  124. 124

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

    CAS  Article  PubMed  Google Scholar 

  125. 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).

    CAS  Article  PubMed  Google Scholar 

  126. 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).

    CAS  Article  PubMed  Google Scholar 

  127. 127

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

    CAS  Article  PubMed  Google Scholar 

  128. 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).

    Article  Google Scholar 

  129. 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).

    Article  PubMed  Google Scholar 

  130. 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).

    Article  Google Scholar 

  131. 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).

    CAS  Article  PubMed  Google Scholar 

  132. 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).

    CAS  Article  PubMed  Google Scholar 

  133. 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).

    Article  Google Scholar 

  134. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

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

    CAS  Article  PubMed  Google Scholar 

  136. 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).

    CAS  Article  Google Scholar 

  137. 137

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

    CAS  Article  PubMed  Google Scholar 

  138. 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).

    CAS  Article  PubMed  Google Scholar 

  139. 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).

    CAS  Article  PubMed  Google Scholar 

  140. 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).

    CAS  Article  PubMed  Google Scholar 

  141. 141

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

    CAS  Article  PubMed  Google Scholar 

  142. 142

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

    CAS  Article  PubMed  Google Scholar 

  143. 143

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

    CAS  Article  PubMed  Google Scholar 

  144. 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).

    Google Scholar 

  145. 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).

    CAS  Article  PubMed  Google Scholar 

  146. 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).

    CAS  Article  PubMed  Google Scholar 

  147. 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).

    Article  PubMed  Google Scholar 

  148. 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).

    CAS  Article  PubMed  Google Scholar 

  149. 149

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

    CAS  Article  PubMed  Google Scholar 

  150. 150

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

    CAS  Article  PubMed  Google Scholar 

  151. 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).

    CAS  Article  PubMed  Google Scholar 

  152. 152

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

    CAS  Article  PubMed  Google Scholar 

  153. 153

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

    CAS  Article  PubMed  Google Scholar 

  154. 154

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

    Article  Google Scholar 

  155. 155

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

    CAS  Article  PubMed  Google Scholar 

  156. 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).

    CAS  Article  PubMed  Google Scholar 

  157. 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).

    CAS  Article  PubMed  Google Scholar 

  158. 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).

    CAS  Article  PubMed  Google Scholar 

  159. 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).

    CAS  Article  PubMed  Google Scholar 

  160. 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).

    CAS  Article  PubMed  Google Scholar 

  161. 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).

    CAS  PubMed  Google Scholar 

  162. 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).

    CAS  Article  PubMed  Google Scholar 

  163. 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).

    CAS  Article  PubMed  Google Scholar 

  164. 164

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

    CAS  Article  PubMed  Google Scholar 

  165. 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).

    CAS  Article  PubMed  Google Scholar 

  166. 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).

    Article  PubMed  Google Scholar 

  167. 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).

    CAS  Article  PubMed  Google Scholar 

  168. 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).

    CAS  Article  PubMed  Google Scholar 

  169. 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).

    CAS  Article  PubMed  Google Scholar 

  170. 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).

    CAS  Article  PubMed  Google Scholar 

  171. 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).

    CAS  Article  PubMed  Google Scholar 

  172. 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).

    CAS  Article  PubMed  Google Scholar 

  173. 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).

    CAS  Article  PubMed  Google Scholar 

  174. 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.

    CAS  Article  PubMed  Google Scholar 

  175. 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).

    CAS  Article  PubMed  Google Scholar 

  176. 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).

    CAS  Article  PubMed  Google Scholar 

  177. 177

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

    CAS  Article  PubMed  Google Scholar 

  178. 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).

    CAS  Article  PubMed  Google Scholar 

  179. 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).

    CAS  Article  PubMed  Google Scholar 

  180. 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).

    CAS  PubMed  Google Scholar 

  181. 181

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

    CAS  Article  PubMed  Google Scholar 

  182. 182

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

    CAS  Article  PubMed  Google Scholar 

  183. 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).

    CAS  Article  PubMed  Google Scholar 

  184. 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).

    CAS  Article  PubMed  Google Scholar 

  185. 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).

    CAS  Article  PubMed  Google Scholar 

  186. 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).

    CAS  Article  PubMed  Google Scholar 

  187. 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).

    CAS  Article  PubMed  Google Scholar 

  188. 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).

    CAS  Article  PubMed  Google Scholar 

  189. 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).

    CAS  Article  PubMed  Google Scholar 

  190. 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).

    Article  PubMed  Google Scholar 

  191. 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).

    CAS  Article  PubMed  Google Scholar 

  192. 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).

    CAS  Article  PubMed  Google Scholar 

  193. 193

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

    CAS  Article  PubMed  Google Scholar 

  194. 194

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

    CAS  Article  PubMed  Google Scholar 

  195. 195

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

    CAS  Article  PubMed  Google Scholar 

  196. 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.

    CAS  Article  PubMed  Google Scholar 

  197. 197

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

    Google Scholar 

  198. 198

    Ito, R., Dalley, J. W., Robbins, T. W. & Everitt, B. J. Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of drug-associated cue. J. Neurosci. 22, 6247–6253 (2002).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

I thank Y. Shaham, B. Hoffer, S. Ikemoto and A. Zangen for critical comments on an earlier draft.

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FURTHER INFORMATION

Encyclopedia of Life Sciences

addiction

cocaine and amphetamines

dopamine

Glossary

NEUROLEPTIC

A drug that blocks the effects of dopamine by binding to and occluding the dopamine receptor.

REINFORCEMENT

The strengthening of stimulus–stimulus, stimulus–response or response–reward associations that results from the timely presentation of a reward. The term applies to both Pavlovian and instrumental conditioning, though it is most frequently used with the latter.

REWARD

In the noun form (a reward), an object or event that elicits approach and is worked for; its analogue is 'a reinforcer'. In the verb form (to reward) the term is synonymous with 'to reinforce'. As a verb it is used with respect to instrumental but not Pavlovian conditioning.

DRIVE

The energizing effects on behaviour of internal stimuli associated with tissue need or hormonal level, or of external stimuli associated with past rewards ('incentive motivational' stimuli).

PRIMING

The precipitation of a learned response habit by administration of an unearned sample of the reward.

SUBSTANTIA NIGRA

Originally named for the pigmented dopamine cells of zona compacta of the substantia nigra (SNc) and ventral tegmental area, the term now designates only the lateral portion of the dopamine cells: those that project to the caudate–putamen. The term has also been extended to include the group of non-pigmented (γ-aminobutyric acid-mediated) substantia nigra pars reticulata (SNr) cells that lies ventral to the SNc and that provides feedback to it.

STRIATUM

In the rat the multiple bundles of the internal capsule give the caudate–putamen and the nucleus accumbens a striated appearance in sagittal section. For this reason they have come to be known as the dorsal and ventral striatum, respectively. The olfactory tubercle, beneath nucleus accumbens, has been recognized as an extension of the ventral striatum.

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Wise, R. Dopamine, learning and motivation. Nat Rev Neurosci 5, 483–494 (2004). https://doi.org/10.1038/nrn1406

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