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Opiate state controls bi-directional reward signaling via GABAA receptors in the ventral tegmental area

Nature Neuroscience volume 7, pages 160–169 (2004)Cite this article

Abstract

The neural mechanisms that mediate the transition from a drug-naive state to a state of drug dependence and addiction are not yet known. Here we show that a discrete population of GABAA receptors in the mammalian ventral tegmental area (VTA) serves as a potential addiction switching mechanism by gating reward transmission through one of two neural motivational systems: either a dopamine-independent (opiate-naive) or a dopaminergic (opiate-dependent or opiate-withdrawn) system. Bi-directional transmission of reward signals through this GABAA receptor substrate is dynamically controlled by the opiate state of the organism and involves a molecular alteration of the GABAA receptor. After opiate exposure and subsequent withdrawal, the functional conductance properties of the rat VTA GABAA receptor switch from an inhibitory to an excitatory signaling mode.

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Figure 1: Histological analysis of intra-VTA and intra-NAc bilateral cannulae placements.
Figure 2: To verify the presence of dopaminergic A10 neurons within the vicinity of VTA cannulae tips, alternate VTA sections were processed for TH immunoreactivity.
Figure 3: Motivational effects of intra-VTA muscimol or bicuculline in the opiate-naive versus opiate-dependent/withdrawn state: role of dopamine signaling.
Figure 4: Time-dependent effects on opiate withdrawal aversions and role of dopamine signaling; effects of GABAB receptor activation on VTA GABAA reward transmission.
Figure 5: Agonist activation of VTA GABAA receptors decreases CREB phosphorylation in the opiate-naive state, but increases CREB phosphorylation in the opiate-dependent/withdrawn state.
Figure 6: Single-unit extracellular recordings of VTA GABAergic neurons shows that a subpopulation of these neurons respond with excitatory depolarization to receptor activation in the opiate-dependent/withdrawn state.
Figure 7: The functional switch in GABAA receptor–mediated reward transmission is dependent upon carbonic anhydrase activity in the opiate-withdrawn state.

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology University of Toronto, Neurobiology Research Group, Ontario, M5S 1A8, Canada

    Steven R Laviolette & Derek van der Kooy

  2. Department of Neuropharmacology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Roger A Gallegos & Steven J Henriksen

  3. Department of Medical Genetics and Microbiology, University of Toronto, Ontario, M5S 1A8, Canada

    Derek van der Kooy

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Correspondence to Steven R Laviolette.

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Laviolette, S., Gallegos, R., Henriksen, S. et al. Opiate state controls bi-directional reward signaling via GABAA receptors in the ventral tegmental area. Nat Neurosci 7, 160–169 (2004). https://doi.org/10.1038/nn1182

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