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:

Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons

Nature volume 437, pages 1027–1031 (2005)Cite this article

Abstract

Drugs of abuse are known to cause persistent modification of neural circuits, leading to addictive behaviours1,2,3,4,5. Changes in synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) may contribute to circuit modification induced by many drugs of abuse, including cocaine6,7,8,9,10,11,12,13. Here we report that, following repeated exposure to cocaine in vivo, excitatory synapses to rat VTA dopamine neurons become highly susceptible to the induction of long-term potentiation (LTP) by correlated pre- and postsynaptic activity. This facilitated LTP induction is caused by cocaine-induced reduction of GABAA (γ-aminobutyric acid) receptor-mediated inhibition of these dopamine neurons. In midbrain slices from rats treated with saline or a single dose of cocaine, LTP could not be induced in VTA dopamine neurons unless GABA-mediated inhibition was reduced by bicuculline or picrotoxin. However, LTP became readily inducible in slices from rats treated repeatedly with cocaine; this LTP induction was prevented by enhancing GABA-mediated inhibition using diazepam. Furthermore, repeated cocaine exposure reduced the amplitude of GABA-mediated synaptic currents and increased the probability of spike initiation in VTA dopamine neurons. This cocaine-induced enhancement of synaptic plasticity in the VTA may be important for the formation of drug-associated memory.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Repeated cocaine exposure facilitates LTP induction in VTA dopamine neurons.
Figure 2: The effect of blocking GABA-mediated inhibition on LTP induction in dopamine neurons.
Figure 3: Effects of cocaine exposure on GABA-mediated inhibition of VTA neurons.
Figure 4: A critical level of GABA-mediated inhibition regulates LTP induction in dopamine neurons.
Figure 5: Comparison of LTP induced by two different protocols and cocaine-induced changes in the AMPA-to-NMDA receptor ratio.

Similar content being viewed by others

References

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

    Article  ADS  CAS  Google Scholar 

  2. Yao, W. D. et al. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioural plasticity. Neuron 41, 625–638 (2004)

    Article  CAS  Google Scholar 

  3. 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 

  4. Thompson, A. M., Gosnell, B. A. & Wagner, J. J. Enhancement of long-term potentiation in the rat hippocampus following cocaine exposure. Neuropharmacology 42, 1039–1042 (2002)

    Article  CAS  Google Scholar 

  5. Robinson, T. E. & Kolb, B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47 (suppl.), 33–46 (2004)

    Article  CAS  Google Scholar 

  6. Kauer, J. A. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu. Rev. Physiol. 66, 447–475 (2004)

    Article  CAS  Google Scholar 

  7. Faleiro, L. J., Jones, S. & Kauer, J. A. Rapid synaptic plasticity of glutamatergic synapses on dopamine neurons in the ventral tegmental area in response to acute amphetamine injection. Neuropsychopharmacology 29, 2115–2125 (2004)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  9. 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)

    Article  CAS  Google Scholar 

  10. Borgland, S. L., Malenka, R. C. & Bonci, A. Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioural correlates in individual rats. J. Neurosci. 24, 7482–7490 (2004)

    Article  CAS  Google Scholar 

  11. Dong, Y. et al. Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioural correlates in GluRA(- / - ) mice. Proc. Natl Acad. Sci. USA 101, 14282–14287 (2004)

    Article  ADS  CAS  Google Scholar 

  12. Wolf, M. E., Sun, X., Mangiavacchi, S. & Chao, S. Z. Psychomotor stimulants and neuronal plasticity. Neuropharmacology 47 (suppl.), 61–79 (2004)

    Article  CAS  Google Scholar 

  13. Kelley, A. E. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44, 161–179 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Jones, S. & Kauer, J. A. Amphetamine depresses excitatory synaptic transmission via serotonin receptors in the ventral tegmental area. J. Neurosci. 19, 9780–9787 (1999)

    Article  CAS  Google Scholar 

  16. Hyland, B. I., Reynolds, J. N., Hay, J., Perk, C. G. & Miller, R. Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience 114, 475–492 (2002)

    Article  CAS  Google Scholar 

  17. 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)

    Article  CAS  Google Scholar 

  18. Wigstrom, H. & Gustafsson, B. Facilitated induction of hippocampal long-lasting potentiation during blockade of inhibition. Nature 301, 603–604 (1983)

    Article  ADS  CAS  Google Scholar 

  19. Huang, Z. J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Meredith, R. M., Floyer-Lea, A. M. & Paulsen, O. Maturation of long-term potentiation induction rules in rodent hippocampus: role of GABAergic inhibition. J. Neurosci. 23, 11142–11146 (2003)

    Article  CAS  Google Scholar 

  22. Pouille, F. & Scanziani, M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Science 293, 1159–1163 (2001)

    Article  CAS  Google Scholar 

  23. Herron, C. E., Williamson, R. & Collingridge, G. L. A selective N-methyl-d-aspartate antagonist depresses epileptiform activity in rat hippocampal slices. Neurosci. Lett. 61, 255–260 (1985)

    Article  CAS  Google Scholar 

  24. Larkum, M. E., Zhu, J. J. & Sakmann, B. A new cellular mechanism for coupling inputs arriving at different cortical layers. Nature 398, 338–341 (1999)

    Article  ADS  CAS  Google Scholar 

  25. Artola, A., Brocher, S. & Singer, W. Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex. Nature 347, 69–72 (1990)

    Article  ADS  CAS  Google Scholar 

  26. Eghbali, M., Curmi, J. P., Birnir, B. & Gage, P. W. Hippocampal GABAA channel conductance increased by diazepam. Nature 388, 71–75 (1997)

    Article  ADS  CAS  Google Scholar 

  27. Stevens, C. F. & Wang, Y. Changes in reliability of synaptic function as a mechanism for plasticity. Nature 371, 704–707 (1994)

    Article  ADS  CAS  Google Scholar 

  28. Bolshakov, V. Y. & Siegelbaum, S. A. Regulation of hippocampal transmitter release during development and long-term potentiation. Science 269, 1730–1734 (1995)

    Article  ADS  CAS  Google Scholar 

  29. Gardner, E. L. et al. Gamma-vinyl GABA, an irreversible inhibitor of GABA transaminase, alters the acquisition and expression of cocaine-induced sensitization in male rats. Synapse 46, 240–250 (2002)

    Article  CAS  Google Scholar 

  30. Brodie, J. D., Figueroa, E. & Dewey, S. L. Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA. Synapse 50, 261–265 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the US National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, California, 94720, Berkeley, USA

    Qing-song Liu, Lu Pu & Mu-ming Poo

Authors
  1. Qing-song Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lu Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mu-ming Poo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Qing-song Liu or Mu-ming Poo.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1–S5 and accompanying legends, which show cocaine-induced locomotor sensitization, the idenfication of dopamine neurons, the effect of bicuculline on EPSPs or EPSCs at different membrane potentials and the effect of biccculline and diazepam on IPSCs in VTA dopamine neurons. (DOC 474 kb)

Supplementary Tables

This file contains Supplementary Tables S1 and S2, which show that repeated cocaine exposure has no signifincant effect on passive membrane properties of VTA dopamine neurons, but increases the probability of spike initiation. (DOC 41 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Qs., Pu, L. & Poo, Mm. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437, 1027–1031 (2005). https://doi.org/10.1038/nature04050

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04050

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

Advanced 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