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Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors

Nature Neuroscience volume 14, pages 15481554 (2011) | Download Citation

Abstract

Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1–induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.

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Acknowledgements

We thank Y. Azriel for preparing the image shown in Figure 1a, and T. Kaneko (Kyoto University) for donating Gad67-GFP mice. This work was supported by the National Health and Medical Research Council of Australia and the National Institute on Drug Abuse Intramural Research Program of the US National Institutes of Health.

Author information

Affiliations

  1. Discipline of Pharmacology, University of Sydney, Sydney, Australia.

    • Elena E Bagley
    •  & MacDonald J Christie
  2. Brain & Mind Research Institute, University of Sydney, Sydney, Australia.

    • Elena E Bagley
    • , Jennifer Hacker
    • , Christophe Mallet
    • , Billy C H Chieng
    • , Julie Perroud
    •  & MacDonald J Christie
  3. National Institute on Drug Abuse, Integrative Neuroscience Section, Baltimore, Maryland, USA.

    • Vladimir I Chefer
    •  & Toni S Shippenberg
  4. School of Psychology, University of New South Wales, Sydney, Australia.

    • Gavan P McNally

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Contributions

E.E.B. designed and performed all of the electrophysiological experiments, with the exception of some of the IPSC experiments, contributed to research design and prepared the manuscript, with contributions from all of the other authors. C.M. performed and analyzed some of the IPSC experiments. J.H. and J.P. performed immunohistochemical and behavioral studies under the supervision and with the direct assistance of B.C.H.C., M.J.C. and G.P.M. G.P.M. also performed and supervised the microinjection studies. V.I.C. and T.S.S. designed and performed all of the microdialysis experiments. M.J.C. contributed to experimental design, supervision, coordinated experimental approaches and preparation of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to MacDonald J Christie.

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DOI

https://doi.org/10.1038/nn.2940

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