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Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system

Nature Neuroscience volume 7, pages 153–159 (2004)Cite this article

Abstract

The rewarding effect of drugs of abuse is mediated by activation of the mesolimbic dopamine system, which is inhibited by putative anti-craving compounds. Interestingly, different GABAB receptor agonists can exert similarly opposing effects on the reward pathway, but the cellular mechanisms involved are unknown. Here we found that the coupling efficacy (EC50) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABAB receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits. Consequently, in rodent VTA slices, a low concentration of the canonical agonist baclofen caused increased activity, whereas higher doses eventually inhibited dopamine neurons. At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse γ-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons. Thus GABAB receptor agonists exert parallel cellular and behavioral effects due to the cell-specific expression of GIRK subunits.

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Figure 1: Pre- and postsynaptic GABAB receptor–mediated inhibition in VTA neurons.
Figure 2: GABAB receptor agonist–evoked currents in VTA neurons are mediated by two distinct conductances.
Figure 3: The Ba-resistant component is an outward rectifying potassium conductance that has a low EC50.
Figure 4: Low efficacy of GABAB receptors in dopaminergic neurons correlates with specific combination of GIRK channel subunits.
Figure 5: Coupling efficiency of GABAB receptors to different combinations of GIRK subunits expressed heterologously in HEK-293T cells.
Figure 6: Bi-directional effects of GABAB receptor agonists on the firing rate of dopamine neurons in the VTA.
Figure 7: GHB-evoked currents in VTA neurons.

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Acknowledgements

We thank the members of the Lüscher lab for many helpful discussions, L. Jan for the GABABR1 and GABABR2 cDNA, D. Clapham for GIRK3 cDNA, M. Lazdunski for GIRK2a cDNA, and A. Gittis for some of the dose-response data. We also thank C. Fiorillo, M. Frerking, and M. Mühlethaler for comments on an earlier version of the manuscript, and F. Loctin for technical assistance. M.L is supported, in part, by the Danish Natural Science Research Council. C.L. is supported by grants of the Swiss National Science Foundation. C.L. and P.A.S. share a Human Science Frontier Project Young Investigator's grant.

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Authors and Affiliations

  1. Department of Basic Neurosciences, University of Geneva, 1 Michel Servet, Geneva, 4, CH-1211, Switzerland

    Hans G Cruz, Tatiana Ivanova & Christian Lüscher

  2. Clinic of Neurology, University of Geneva, 1 Michel Servet, Geneva, 4, CH-1211, Switzerland

    Christian Lüscher

  3. Peptide Biology Laboratory, The Salk Institute for Biological Studies, Box 85800, San Diego, 92186, California, USA

    Marie-Louise Lunn & Paul A Slesinger

  4. Laboratory of Metabolic Diseases, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Markus Stoffel

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Supplementary information

Supplementary Fig. 1

GIRK current desensitization in DA neurons of the VTA is a function of agonist concentration. (a) Representative traces at baclofen concentrations as indicated. Scale bar 2.5 min/200 pA. (b) Average desensitization after 15 min of continuous baclofen application at increasing concentration (n > 5 for each point). Note that below 1 μM, no desensitization was observed. (GIF 5 kb)

Supplementary Fig. 2

Differential coupling efficacy (EC50) of GIRK channels in VTA neurons is sufficient to explain bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system. The VTA contains dopamine neurons that are under inhibitory control by local GABA neurons. Both cell types receive excitatory (mainly from the prefrontal cortex and the pedunculo pontine tegmental nucleus; not drawn) and inhibitory inputs (from the pallidum (GP) and nucleus accumbens, NAc)41. In the acute slice preparation all these distant afferents are cut, leaving local GABA neurons to exert an inhibitory control of dopamine neurons. Since dopamine neurons are less sensitive to GABABR agonists than GABA neurons (note significantly higher EC50 for baclofen compared to the EC50 of pre- as well as postsynaptic inhibition in GABA neurons) low agonist concentrations will lead to disinhibition while at higher concentrations both cell types will stop firing. (JPG 71 kb)

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Cruz, H., Ivanova, T., Lunn, ML. et al. Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system. Nat Neurosci 7, 153–159 (2004). https://doi.org/10.1038/nn1181

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