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.

Opioids block long-term potentiation of inhibitory synapses

Nature volume 446, pages 1086–1090 (2007)Cite this article

Abstract

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning1. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (γ-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABAA-mediated synaptic transmission (LTPGABA) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTPGABA by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTPGABA. Whereas brief treatment with morphine in vitro blocks LTPGABA by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABAA receptors.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Figure 1: GABAergic synapses on dopamine neurons are potentiated after HFS.
Figure 2: Chelating postsynaptic Ca 2+ or blocking NMDARs prevents LTP GABA , whereas GABA A receptor activation is not required.
Figure 3: LTP GABA requires NO–cGMP signalling.
Figure 4: Opioids block LTP GABA both in vitro and in vivo by distinct mechanisms.

References

  1. Malenka, R. C. & Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004)

    CAS  Article  Google Scholar 

  2. Yim, C. Y. & Mogenson, G. Electrophysiological studies of neurons in the ventral tegmental area of Tsai. Brain Res. 181, 301–313 (1980)

    CAS  Article  Google Scholar 

  3. Johnson, S. W. & North, R. A. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 12, 483–488 (1992)

    CAS  Article  Google Scholar 

  4. Zalutsky, R. A. & Nicoll, R. A. Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248, 1619–1624 (1990)

    ADS  CAS  Article  Google Scholar 

  5. Stern, J. E. & Ludwig, M. NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs. Am. J. Physiol. 28, R1815–R1822 (2001)

    Google Scholar 

  6. Li, D. P., Chen, S. R. & Pan, H. L. Nitric oxide inhibits spinally projecting paraventricular neurons through potentiation of presynaptic GABA release. J. Neurophysiol. 88, 2664–2674 (2002)

    CAS  Article  Google Scholar 

  7. Yu, D. & Eldred, W. D. Nitric oxide stimulates γ-aminobutyric acid release and inhibits glycine release in retina. J. Comp. Neurol. 483, 278–291 (2005)

    CAS  Article  Google Scholar 

  8. Klejbor, I., Domaradzka-Pytel, B., Ludkiewicz, B., Wojcik, S. & Morys, J. The relationships between neurons containing dopamine and nitric oxide synthase in the ventral tegmental area. Folia Histochem. Cytobiol. 42, 83–87 (2004)

    CAS  PubMed  Google Scholar 

  9. Brenman, J. E. & Bredt, D. S. Synaptic signaling by nitric oxide. Curr. Opin. Neurobiol. 7, 374–378 (1997)

    CAS  Article  Google Scholar 

  10. Safo, P. K., Cravatt, B. F. & Regehr, W. G. Retrograde endocannabinoid signaling in the cerebellar cortex. Cerebellum 5, 134–145 (2006)

    CAS  Article  Google Scholar 

  11. Aizenman, C. D., Manis, P. B. & Linden, D. J. Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse. Neuron 21, 827–835 (1998)

    CAS  Article  Google Scholar 

  12. Shew, T., Yip, S. & Sastry, B. R. Mechanisms involved in tetanus-induced potentiation of fast IPSCs in rat hippocampal CA1 neurons. J. Neurophysiol. 83, 3388–3401 (2001)

    Article  Google Scholar 

  13. Komatsu, Y. GABAB receptors, monoamine receptors, and postsynaptic inositol trisphosphate-induced Ca2+ release are involved in the induction of long-term potentiation at visual cortical inhibitory synapses. J. Neurosci. 16, 6342–6352 (1996)

    CAS  Article  Google Scholar 

  14. Ouardouz, M. & Sastry, B. R. Mechanisms underlying LTP of inhibitory synaptic transmission in the deep cerebellar nuclei. J. Neurophysiol. 84, 1414–1421 (2000)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  16. 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)

    ADS  CAS  Article  Google Scholar 

  17. 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  Google Scholar 

  18. 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)

    CAS  Article  Google Scholar 

  19. Liu, Q. S., Pu, L. & Poo, M. M. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437, 1027–1031 (2005)

    ADS  CAS  Article  Google Scholar 

  20. Bonci, A. & Williams, J. T. A common mechanism mediates long-term changes in synaptic transmission after chronic cocaine and morphine. Neuron 16, 631–639 (1996)

    CAS  Article  Google Scholar 

  21. Shoji, Y., Delfs, J. & Williams, J. T. Presynaptic inhibition of GABAB-mediated synaptic potentials in the ventral tegmental area during morphine withdrawal. J. Neurosci. 19, 2347–2355 (1999)

    CAS  Article  Google Scholar 

  22. Melis, M., Camarini, R., Ungless, M. A. & Bonci, A. Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure. J. Neurosci. 22, 2074–2082 (2002)

    CAS  Article  Google Scholar 

  23. Margolis, E. B. et al. κ opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc. Natl Acad. Sci. USA 103, 2938–2942 (2006)

    ADS  CAS  Article  Google Scholar 

  24. Schulteis, G., Heyser, C. J. & Koob, G. F. Opiate withdrawal signs precipitated by naloxone following a single exposure to morphine: potentiation with a second morphine exposure. Psychopharmacology 129, 56–65 (1997)

    CAS  Article  Google Scholar 

  25. Vanderschuren, L. J., De Vries, T. J., Wardeh, G., Hogemboom, F. A. & Schoffelmeer, A. N. A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats. Eur. J. Neurosci. 14, 1533–1538 (2001)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  27. Williams, J. T., Christie, M. J. & Manzoni, O. Cellular and synaptic adaptations mediating opioid dependence. Physiol. Rev. 81, 299–343 (2001)

    CAS  Article  Google Scholar 

  28. Stromberg, M. F., Mackler, S. A., Volpicelli, J. R., O’Brien, C. P. & Dewey, S. L. The effect of γ-vinyl-GABA on the consumption of concurrently available oral cocaine and ethanol in the rat. Pharmacol. Biochem. Behav. 68, 291–299 (2001)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  30. Barrett, A. C., Negus, S. S., Mello, N. K. & Caine, S. B. Effect of GABA agonists and GABA-A receptor modulators on cocaine- and food-maintained responding and cocaine discrimination in rats. J. Pharmacol. Exp. Ther. 315, 858–871 (2005)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants to J.A.K. and E.C.P. We are grateful to B. Connors and C. Aizenman for discussions and to J. Downing-Park for technical assistance.

Author information

Author notes

  1. Esther C. Penick

    Present address: Present address: Knox College, 2 East South Street, Galesburg, Illinois 61401, USA.,

  2. Fereshteh S. Nugent and Esther C. Penick: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Pharmacology, Brown University, Physiology and Biotechnology, Providence, Rhode Island 02912, USA,

    Fereshteh S. Nugent, Esther C. Penick & Julie A. Kauer

Authors
  1. Fereshteh S. Nugent
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esther C. Penick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julie A. Kauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julie A. Kauer.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-3 with Legends, Supplementary Methods and additional references. (PDF 1782 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nugent, F., Penick, E. & Kauer, J. Opioids block long-term potentiation of inhibitory synapses. Nature 446, 1086–1090 (2007). https://doi.org/10.1038/nature05726

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05726

Further reading

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