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

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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.