This research will characterize the behavioral pharmacology of novel benzodiazepine (BZ) receptor partial/selective agonists and inverse agonists in baboons and rats. Over the five-year project period, studies in four areas related to the abuse and behavioral toxicity of BZs will be conducted concurrently. One set of studies will involve intravenous self-injection in baboons. A study will extend previous research showing unusually high rates of self-injection of the novel agonist zolpidem by comparing zolpidem with other sedatives (triazolam and pentobarbital) under different conditions of availability (limited access; ad libitum; progressive-ratio schedule). Other self-injection studies will characterize reinforcement and/or punishment by intravenous injections of BZ receptor ligands. These studies will provide information about the abuse liability and patient acceptability of these compounds. A second set of studies will assess gross behavioral effects of these drugs by using observational methods in baboons and schedule- controlled behavior in baboons and rats. These studies will provide information about the behavior-impairing and sedative or stimulant effects of these compounds. The comparison of data in baboons and rats will provide critical information about the cross species generality of effects. A third set of studies will examine the extent to which the partial/selective agonists and inverse agonists can precipitate withdrawal in baboons physically dependent on a BZ (lorazepam). These studies will provide information about the nature of BZ physical dependence and whether chronic BZ-using patients could be at risk from acute administration of some of the novel compounds. A final set of studies will use procedures for assessing repeated acquisition and retention of response chains in baboons as a baseline for characterizing anterograde amnestic effects of triazolam and various BZ receptor ligands. In addition to examining memory impairing effects, these studies may detect possible memory enhancing effects of inverse agonists. By constructing full dose-effect curves to permit examination of relative potencies of compounds across the different behavioral measures and by examining drug interactions among agonists, partial/selective agonists and inverse agonists, these studies will provide new information about the heterogeneity of action and molecular mechanisms of action of compounds acting at the GABA/BZ chloride ionophore receptor complex. there is concern about the abuse and behavioral toxicity of BZ anxiolytic-sedative drugs, which are widely prescribed psychotropic medications. These studies should contribute to efforts to develop and identify new classes of anxiolytic-sedative compounds which have reduced potential for abuse and behavioral toxicity. More generally, the data from this project will contribute to a scientific understanding of anxiolytic-sedative drug abuse and will ultimately contribute to the development of improved prevention, control and treatment procedures.
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