Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons

Abstract

How do drugs of abuse modify neural circuitry and thereby lead to addictive behaviour? As for many forms of experience-dependent plasticity, modifications in glutamatergic synaptic transmission have been suggested to be particularly important1,2,3,4. Evidence of such changes in response to in vivo administration of drugs of abuse is lacking, however. Here we show that a single in vivo exposure to cocaine induces long-term potentiation of AMPA (α-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated currents at excitatory synapses onto dopamine cells in the ventral tegmental area. Potentiation is still observed 5 but not 10 days after cocaine exposure and is blocked when an NMDA (N-methyl-d-aspartate) receptor antagonist is administered with cocaine. Furthermore, long-term potentiation at these synapses is occluded and long-term depression is enhanced by in vivo cocaine exposure. These results show that a prominent form of synaptic plasticity can be elicited by a single in vivo exposure to cocaine and therefore may be involved in the early stages of the development of drug addiction.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A single exposure to cocaine induced an increase in the AMPAR/NMDAR ratio of glutamatergic synaptic currents in VTA dopamine cells.
Figure 2: Cocaine exposure had no effect on paired-pulse modulation but increased mEPSC frequency and mEPSC amplitude.
Figure 3: Cocaine exposure caused a larger response to AMPA but not NMDA and did not change the total amount of AMPAR subunits.
Figure 4: Cocaine-induced increase in AMPAR/NMDAR ratio in the VTA lasted for 5 but not 10 days after injection and did not occur in the hippocampus or in GABA neurons in the VTA.
Figure 5: Cocaine-induced potentiation was blocked by the NMDAR antagonist MK-801, occluded LTP and enhanced LTD.

Similar content being viewed by others

References

  1. Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 25, 515–532 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Kalivas, P. W. Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants. Drug Alcohol Depend. 37, 95–100 (1995).

    Article  CAS  Google Scholar 

  4. Clark, D. & Overton, P. G. Alterations in excitatory amino acid-mediated regulation of midbrain dopaminergic neurons induced by chronic psychostimulant administration and stress: relevance to behavioural sensitization and drug addiction. Addict. Biol. 3, 109–135 (1998).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. Jones, S., Kornblum, J. L. & Kauer, J. A. Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J. Neurosci. 20, 5575–5580 (2000).

    Article  CAS  Google Scholar 

  9. Johnson, S. W. & North, R. A. Two types of neurone in the rat ventral tegmental area and their synaptic inputs. J. Physiol. 450, 455–468 (1992).

    Article  CAS  Google Scholar 

  10. Perkel, D. J. & Nicoll, R. A. Evidence for all-or-none regulation of neurotransmitter release: implications for long-term potentiation. J. Physiol. 471, 481–500 (1993).

    Article  CAS  Google Scholar 

  11. Dobrunz, L. E. & Stevens, C. F. Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron 18, 995–1008 (1997).

    Article  CAS  Google Scholar 

  12. Malenka, R. C. & Nicoll, R. A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  Google Scholar 

  13. Isaac, J. T., Nicoll, R. A. & Malenka, R. C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 (1995).

    Article  CAS  Google Scholar 

  14. Liu, G., Choi, S. & Tsien, R. W. Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices. Neuron 22, 395–409 (1999).

    Article  CAS  Google Scholar 

  15. Choi, S., Klingauf, J. & Tsien, R. W. Postfusional regulation of cleft glutamate concentration during LTP at ‘silent synapses’. Nature Neurosci. 3, 330–336 (2000).

    Article  CAS  Google Scholar 

  16. Fitzgerald, L. W., Ortiz, J., Hamedani, A. G. & Nestler, E. J. Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents. J. Neurosci. 16, 274–282 (1996).

    Article  CAS  Google Scholar 

  17. Shi, S. H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816 (1999).

    Article  CAS  Google Scholar 

  18. Barria, A., Muller, D., Derkach, V., Griffith, L. C. & Soderling, T. R. Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science 276, 2042–2045 (1997).

    Article  CAS  Google Scholar 

  19. 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).

    Article  ADS  CAS  Google Scholar 

  20. White, F. J. & Wang, R. Y. Electrophysiological evidence for A10 dopamine autoreceptor subsensitivity following chronic D-amphetamine treatment. Brain Res. 309, 283–292 (1984).

    Article  CAS  Google Scholar 

  21. Zhang, X. F., Hu, X. T., White, F. J. & Wolf, M. E. Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors. J. Pharmacol. Exp. Ther. 281, 699–706 (1997).

    CAS  PubMed  Google Scholar 

  22. Thomas, M. J., & Malenka, R. C. Behavioral sensitization to cocaine is associated with changes in nucleus accumbens excitatory synaptic transmission. Soc. Neurosci. Abstr. 292.3 (2000).

  23. Jackson, H. C. & Nutt, D. J. A single preexposure produces sensitization to the locomotor effects of cocaine in mice. Pharmacol. Biochem. Behav. 45, 733–735 (1993).

    Article  CAS  Google Scholar 

  24. Kalivas, P. W. & Alesdatter, J. E. Involvement of N-methyl-D-aspartate receptor stimulation in the ventral tegmental area and amygdala in behavioral sensitization to cocaine. J. Pharmacol. Exp. Ther. 267, 486–495 (1993).

    CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  26. Kalivas, P. W. & Duffy, P. D1 receptors modulate glutamate transmission in the ventral tegmental area. J. Neurosci. 15, 5379–5388 (1995).

    Article  CAS  Google Scholar 

  27. Carlezon, W. A. et al. Sensitization to morphine induced by viral-mediated gene transfer. Science 277, 812–814 (1997).

    Article  CAS  Google Scholar 

  28. Mansvelder, H. D. & McGehee, D. S. Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27, 349–357 (2000).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Nicola and H. Fields for comments on this manuscript, members of the Bonci and Malenka labs for discussions, and J. Kim for help with injections. This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A.B. and J.L.W) and by grants from the NIH (R.C.M.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Antonello Bonci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ungless, M., Whistler, J., Malenka, R. et al. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001). https://doi.org/10.1038/35079077

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35079077

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing