Gamma-Hydroxybutyric acid (GHB) occurs endogenously in the brain where it is thought to be a neurotransmitter. GHB is used clinically for treating alcoholism and narcolepsy and is used non-medicinally, both as a primary drug of abuse (presumably because of its sedative/hypnotic effects) and as a sedating agent in unsuspecting victims (e.g., """"""""date rate drug""""""""). Despite GHB having been described more than 30 years ago and despite its widespread use, both medicinally and non-medicinally, relatively little is known about the mechanism that mediates the various effects of GHB. A GHB-associated binding site has been reported, although it is not known whether this site mediates the abuse- related effects of GHB. The paucity of information on the mechanism(s) of action of GHB results from a very limited set of relevant compounds that are available for studying this neurobiologic system and the absence of pharmacologically selective and validated neurochemical and behavioral procedures for characterizing the effects of GHB and related compounds. To that end, the studies proposed in this application will first characterize the receptor binding and behavioral effects of GHB and related compounds. Second, these studies will design and synthesize new compounds for studying the pharmacology of GHB. The working hypothesis of these multidisciplinary studies is that the behavioral effects of GHB are due to its actions on specific sites in brain that are not related to either GABAA or GABAB receptors. Studies under Specific Aim I will design and synthesize potent and selective agonists and antagonists for GHB receptors.
Specific Aim II will characterize the binding of GHB and other compounds, including compounds that are synthesized under Specific Aim I, to specific sites in rat brain that have been characterized by our group with [3H]NCS-382. The functional consequences of GHB binding will be examined under Specific Aim III, including a characterization of the effects of GHB and other compounds on schedule-controlled behavior and an evaluation of discriminative stimulus effects of GHB. These systematic characterizations of the binding and behavioral effects of GHB and the development of newly-synthesized compounds for GHB receptors will provide important new information regarding the mechanisms that mediate effects of GHB and related compounds.
Showing the most recent 10 out of 22 publications
