Gamma-hydroxybutyric acid (GHB) is an endogenous brain substance that in recent years has become more and more popular as an illicit recreational drug for the euphoric sensation that it produces, despite the serious side effects and the potential for dependence that are associated with its intake. The goal of this proposal is to characterize the electrophysiological actions of GHB in the ventral tegmental area and nucleus accumbens, two key areas of the brain reward system, as only very limited electrophysiological data is available on GHB effects in these brain regions. To achieve this goal, the following in vitro investigations will be carried out in projection neurones and interneurones of these two areas using patch electrode recordings: i) analysis of GHB effects on intrinsic voltage-dependent Na+, K+ and Ca2+ currents, and ii) analysis of GHB action on excitatory and inhibitory synaptic currents originating from extrinsic and intrinsic afferents, and their long term potentiation/depression, where present. Using carefully selected combinations of available pharmacological tools, particular attention will be devoted to identify whether GHB and/or GABAB receptors are involved in each of the observed GHB effects, as behavioural, biochemical and electrophysiological evidence in other brain areas suggest an involvement of both receptors in the pharmacological actions of GHB. By characterizing the changes in membrane currents in neurones of the nucleus accumbens and ventral tegmental area following exposure to GHB, and by identifying the location and nature of the receptors involved, this study will provide the basic information necessary to understand GHB-elicited modifications in neuronal excitability in two key areas of the brain reward system, and thus would, for the first time, allow us to draw a detailed picture of the cellular mechanisms underlying the action of this potential drug of abuse.
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| Gervasi, Nicolas; Monnier, Zohreh; Vincent, Pierre et al. (2003) Pathway-specific action of gamma-hydroxybutyric acid in sensory thalamus and its relevance to absence seizures. J Neurosci 23:11469-78 |
