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Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior

Nature Neuroscience volume 20, pages 438448 (2017) | Download Citation

  • A Corrigendum to this article was published on 26 July 2017

This article has been updated

Abstract

Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABAB receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.

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Change history

  • 27 March 2017

    In the version of this article initially published, the y-axis scale in Figure 4c was labeled 0–150 instead of 0–300, the gray data points in Figure 6g were duplicates of the black data points in Figure 6f, and the error bars were missing from the green trace in Figure 7e. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank members of the Bonci lab for insightful discussions and careful reading of the manuscript. We thank the NIDA Histology Core for help with in situ hybridization experiments, B. Sadacca for help with statistical analysis, K. Deisseroth (Stanford University) for the generation of optogenetic constructs, and B. Lowell (Beth Israel Deaconess Medical Center) for Dyn-Cre and VGAT-Cre transgenic mice. This work was supported by the Intramural Research Program at the National Institute on Drug Abuse.

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Affiliations

  1. Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.

    • Nicholas J Edwards
    • , Hugo A Tejeda
    • , Marco Pignatelli
    • , Shiliang Zhang
    • , Ross A McDevitt
    • , Jocelyn Wu
    • , Marisela Morales
    •  & Antonello Bonci
  2. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.

    • Caroline E Bass
  3. Department of Biomedicine, Pharmazentrum, University of Basel, Basel, Switzerland.

    • Bernhard Bettler
  4. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Antonello Bonci
  5. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Antonello Bonci

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Contributions

N.J.E., A.B., H.A.T., R.A.M., M.M.and M.P. designed the experiments. N.J.E. performed electrophysiological and behavioral experiments. J.W. determined virus localizations and S.Z. performed electron microscopy experiments. B.B. provided critical reagents. N.J.E. analyzed the data. N.J.E. and A.B. wrote the paper with contributions from all of the other authors.

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The authors declare no competing financial interests.

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Correspondence to Antonello Bonci.

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https://doi.org/10.1038/nn.4482

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