Article | Published:

Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine

Nature Neurosciencevolume 4pages12171223 (2001) | Download Citation



A compelling model of experience-dependent plasticity is the long-lasting sensitization to the locomotor stimulatory effects of drugs of abuse. Adaptations in the nucleus accumbens (NAc), a component of the mesolimbic dopamine system, are thought to contribute to this behavioral change. Here we examine excitatory synaptic transmission in NAc slices prepared from animals displaying sensitization 10–14 days after repeated in vivo cocaine exposure. The ratio of AMPA (α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) receptor- to NMDA (N-methyl-d-aspartate) receptor-mediated excitatory postsynaptic currents (EPSCs) was decreased at synapses made by prefrontal cortical afferents onto medium spiny neurons in the shell of the NAc. The amplitude of miniature EPSCs at these synapses also was decreased, as was the magnitude of long-term depression. These data suggest that chronic in vivo administration of cocaine elicits a long-lasting depression of excitatory synaptic transmission in the NAc, a change that may contribute to behavioral sensitization and addiction.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Nestler, E. J. Molecular basis of long-term plasticity underlying addiction. Nat. Rev. Neurosci. 2, 119–128 (2001).

  2. 2

    Robinson, T. E. & Berridge, K. C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain. Res. Brain. Res. Rev. 18, 247–291 (1993).

  3. 3

    Wolf, M. E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog. Neurobiol. 54, 679–720 (1998).

  4. 4

    Vanderschuren, L. J. & Kalivas, P. W. Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology (Berl.) 151, 99–120 (2000).

  5. 5

    Schenk, S. & Snow, S. Sensitization to cocaine's motor activating properties produced by electrical kindling of the medial prefrontal cortex but not of the hippocampus. Brain Res. 659, 17–22 (1994).

  6. 6

    Ungless, M. A., Whisler, J. L., Malenka, R. C. & Bonci, A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001).

  7. 7

    Pierce, R. C., Bell, K., Duffy, P. & Kalivas, P. W. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J. Neurosci. 16, 1550–1560 (1996).

  8. 8

    Pierce, R. C., Reeder, D. C., Hicks, J., Morgan, Z. R. & Kalivas, P. W. Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine. Neuroscience 82, 1103–1114 (1998).

  9. 9

    Li, Y. & Wolf, M. E. Ibotenic acid lesions of prefrontal cortex do not prevent expression of behavioral sensitization to amphetamine. Behav. Brain. Res. 84, 285–289 (1997).

  10. 10

    Nicola, S. M., Kombian, S. B. & Malenka, R. C. Psychostimulants depress excitatory synaptic transmission in the nucleus accumbens via presynaptic D1-like dopamine receptors. J. Neurosci. 16, 1591–1604 (1996).

  11. 11

    Zahm, D. S. Functional-anatomical implications of the nucleus accumbens core and shell subterritories. Ann. NY Acad. Sci. 877, 113–128 (1999).

  12. 12

    Zucker, R. S. Short-term synaptic plasticity. Annu. Rev. Neurosci. 12, 13–31 (1989).

  13. 13

    Sah, P., Hestrin, S. & Nicoll, R. A. Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246, 815–818 (1989).

  14. 14

    Malenka, R. C. & Nicoll, R. A. Silent synapses speak up. Neuron 19, 473–476 (1997).

  15. 15

    Kullmann, D. M. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. Neuron 12, 1111–1120 (1994).

  16. 16

    Goda, Y. & Stevens, C. F. Two components of transmitter release at a central synapse. Proc. Natl. Acad. Sci. USA 91, 12942–12946 (1994).

  17. 17

    Oliet, S. H., Malenka, R. C. & Nicoll, R. A. Bidirectional control of quantal size by synaptic activity in the hippocampus. Science 271, 1294–1297 (1996).

  18. 18

    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).

  19. 19

    Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2, 315–324 (2001).

  20. 20

    Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).

  21. 21

    Segal, D. S. & Schuckit, M. A. in Stimulants: Neurochemical, Behavioral and Clinical Perspectives (ed. Creese, I.) 131–167 (Raven, New York, 1983).

  22. 22

    White, F. J., Hu, X. T., Zhang, X. F. & Wolf, M. E. Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J. Pharmacol. Exp. Ther. 273, 445–454 (1995).

  23. 23

    Zhang, X. F., Hu, X. T. & White, F. J. Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. J. Neurosci. 18, 488–498 (1998).

  24. 24

    Lu, W., Chen, H., Xue, C. J. & Wolf, M. E. Repeated amphetamine administration alters the expression of mRNA for AMPA receptor subunits in rat nucleus accumbens and prefrontal cortex. Synapse 26, 269–280 (1997).

  25. 25

    Lu, W. & Wolf, M. E. Repeated amphetamine administration alters AMPA receptor subunit expression in rat nucleus accumbens and medial prefrontal cortex. Synapse 32, 119–131 (1999).

  26. 26

    Churchill, L., Swanson, C. J., Urbina, M. & Kalivas, P. W. Repeated cocaine alters glutamate receptor subunit levels in the nucleus accumbens and ventral tegmental area of rats that develop behavioral sensitization. J. Neurochem. 72, 2397–2403 (1999).

  27. 27

    Bibb, J. A. et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001).

  28. 28

    Kelz, M. B. et al. Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

  29. 29

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

  30. 30

    Pennartz, C. M., Groenewegen, H. J. & Lopes da Silva, F. H. The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog. Neurobiol. 42, 719–761 (1994).

  31. 31

    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).

  32. 32

    McGinty, J. F., ed. Advancing from the Ventral Striatum to the Extended Amygdala: Implications for Neuropsychiatry and Drug Abuse Vol. 877 (New York Academy of Sciences, New York, New York, 1999).

  33. 33

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

  34. 34

    McKinzie, D. L., Rodd-Henricks, Z. A., Dagon, C. T., Murphy, J. M. & McBride, W. J. Cocaine is self-administered into the shell region of the nucleus accumbens in Wistar rats. Ann. NY Acad. Sci. 877, 788–791 (1999).

  35. 35

    Pontieri, F. E. et al. Psychostimulant drugs increase glucose utilization in the shell of the rat nucleus accumbens. Neuroreport 5, 2561–2564 (1994).

  36. 36

    Pontieri, F. E., Tanda, G. & Di Chiara, G. Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc. Natl. Acad. Sci. USA 92, 12304–12308 (1995).

  37. 37

    Caine, S. B., Heinrichs, S. C., Coffin, V. L. & Koob, G. F. Effects of the dopamine D-1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat. Brain Res. 692, 47–56 (1995).

  38. 38

    Pierce, R. C. & Kalivas, P. W. Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine. J. Pharmacol. Exp. Ther. 275, 1019–1029 (1995).

  39. 39

    Parkinson, J. A., Olmstead, M. C., Burns, L. H., Robbins, T. W. & Everitt, B. J. Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. J. Neurosci. 19, 2401–2411 (1999).

  40. 40

    Robinson, T. E. & Kolb, B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J. Neurosci. 17, 8491–8497 (1997).

  41. 41

    Robinson, T. E. & Kolb, B. Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur. J. Neurosci. 11, 1598–1604 (1999).

  42. 42

    Rogan, M. T., Staubli, U. V. & LeDoux, J. E. Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604–607 (1997).

  43. 43

    McKernan, M. G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).

  44. 44

    Moser, E. I., Krobert, K. A., Moser, M. B. & Morris, R. G. Impaired spatial learning after saturation of long-term potentiation. Science 281, 2038–2042 (1998).

  45. 45

    Andersen, P., Moser, E., Moser, M. B. & Trommald, M. Cellular correlates to spatial learning in the rat hippocampus. J. Physiol. (Paris) 90, 349 (1996).

  46. 46

    Rioult-Pedotti, M. S., Friedman, D. & Donoghue, J. P. Learning-induced LTP in neocortex. Science 290, 533–536 (2000).

  47. 47

    Hyman, S. E. & Malenka, R. C. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat. Rev. Neurosci. 2, 695–703 (2001).

Download references


This work was supported by grants from NIDA (R.M., M.T.) and the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A.B.). We thank T. Robinson, S. Nicola and G. Hjelmstad for comments on the paper and D. Saal for help with some experiments.

Author information


  1. Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University School of Medicine, Palo Alto, 94304, California, USA

    • Mark J. Thomas
    • , Corinne Beurrier
    •  & Robert C. Malenka
  2. Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, 94110, California, USA

    • Antonello Bonci


  1. Search for Mark J. Thomas in:

  2. Search for Corinne Beurrier in:

  3. Search for Antonello Bonci in:

  4. Search for Robert C. Malenka in:

Corresponding author

Correspondence to Robert C. Malenka.

About this article

Publication history




Issue Date


Further reading