Gamma-hydroxybutyrate (GHB) is an endogenous substance that binds to specific GHB receptors where it is thought to act as a neurotransmitter/neuromodulator. GHB is used therapeutically, to treat the sleep disorder narcolepsy and to treat alcoholism, and recreationally, as a """"""""club drug"""""""". However, neither the physiological role of GHB, nor the mechanisms for its therapeutic actions and its abuse are understood. This stems in part from the complex pharmacology of GHB, which is thought to act at GABAs and at GHB receptors. To advance our knowledge of the mechanisms underlying the therapeutic utility of GHB and its abuse, research under this grant has used drug discrimination procedures to develop more selective behavioral assays for studying the neuropharmacology of GHB. Using these assays, we obtained further evidence that, instead of GHB receptors, GABAB receptors are prominently involved in the discriminative stimulus effects of GHB. Also, although GHB shares many effects with the prototypical GABAB agonist baclofen, we obtained further evidence that their effects are not identical and perhaps not mediated by the same GABAB mechanisms. Whereas baclofen directly activates GABAs receptors, both GABAB receptor activation and modulation could conceivably be involved in the effects of GHB. There is currently much interest in GABAe receptor positive modulators, because modulation may offer advantages over direct activation of receptors, as exemplified by the benzodiazepines at GABAA receptors. This competing renewal is aimed at further examining similarities and differences between the discriminative stimulus effects of GHB, baclofen, and recently described GABAs positive modulators by studying i) whether GABAe receptor positive modulators produce or enhance GHB- and baclofen-like discriminative stimulus effects (SPECIFIC AIM I), and 2) by further characterizing the discriminative stimulus effects of GABAB receptor positive modulators as training drugs (SPECIFIC AIM II). Based on evidence that GHB may interact synergistically with other club drugs (i.e., the NMDA antagonist ketamine), the present application will also characterize interactions between NMDA antagonists and GHB and related compounds, as well as GABA-ergic compounds (SPECIFIC AIM III). This will increase our understanding of the interactions between the glutamatergic system, which is thought to play an important role in modulating/mediating effects of drugs of abuse, and the GABAB systems involved in the behavioral effects of GHB. The contributions of these studies extend beyond substance abuse to how GABAB mechanisms might contribute to the therapeutic actions of GHB, a systematic characterization of the behavioral effects of GABAB positive modulators, and analysis of interactions between GABAB and glutamatergic systems. Increased knowledge about the activation and modulation of GABAB systems will help to develop effective approaches to treating sleep-, drug abuse-, and other CNS disorders.
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