Recreational use of gamma-hydroxybutyrate (GHB) is increasing dramatically. The pharmacological mechanisms by which GHB produces its abuse-related effects are poorly understood. GHB abuse is likely related to its subjective effects, and subjective effects of drugs in humans can often be predicted from drug discrimination experiments in animals. The discriminative stimulus effects of GHB are likely to be multidimensional and to involve several different receptor mechanisms. Some of these mechanisms may be unique to GHB (i.e., those involving specific GHB receptors), whereas others may be in common with other compounds (i.e., those involving GABAA and GABAB receptors). The studies proposed here will examine the involvement of these mechanisms in the discriminative stimulus effects of GHB under various conditions. Studies under Specific Aim I examine the ability of positive GABAA modulators and agonists at GABAA, GABAB and GHB receptors to substitute for GHB, and the ability of negative GABAA modulators and antagonists at GABAA, GABAB and GHB receptors to attenuate the discriminative stimulus effects of GHB. These substitution and antagonism studies are conducted under conditions involving different training doses of GHB, because the training dose often affects the pharmacological selectivity of the discrimination. Not only the training dose, but also the alterative training condition can affect the pharmacological selectivity, as shown by drug-drug discrimination studies. Studies under Specific Aim II attempt to increase the pharmacological selectivity of the discriminative stimulus effects of GHB by training to discriminate GHB not only from saline, but also from other drugs that share receptor mechanisms with GHB. It is hypothesized that 1) GABAA, GABAB, and GHB receptors each are involved in the discriminative stimulus of GHB, 2) when a low training dose is used the role of GABAA receptors is more prominent, and when a high training dose is used the discrimination will primarily involve GABAB and GHB receptors, and 3) when a high dose of GHB can be discriminated from a GABAB agonist, its discriminative stimulus effects will involve only GHB receptors. By identifying the role of specific receptors in abuse-related effects of GHB, future studies may be better able to develop specific, pharmacologically targeted therapies for GHB abuse.
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