Benzodiazepines are among a growing set of compounds that exert many of their effects by actions at the gamma-amino butyric acid (GABA)A receptor complex. Benzodiazepines are widely used for hypnosis and for anxiety-related disorders; however, long term use of these drugs can generate clinically-significant physical dependence. Moreover, there is increasing evidence for the co-abuse of benzodiazepines and other psychoactive drugs especially among individuals with a history of alcohol or sedative/hypnotic abuse. One major goal of this project is to develop a procedure for studying the discriminative stimulus (subjective) effects of benzodiazepine dependence and withdrawal in rhesus monkeys and, during the last period of support, such a procedure was developed. In the continuation of this project, separate groups of diazepam-treated, zolpidem-treated and untreated monkeys will be used to investigate three general issues using measures of drug discrimination, ventilation and neuroendocrine activity. First, GABAA modulators will be used to test hypotheses regarding selectivity of drug action and variations in efficacy. Although much is known about the molecular actions of GABAA modulators in vitro, very little is known about the clinical ramifications of those findings. These studies will provide a bridge from molecular studies to clinical applications by using a non-human primate model of subjective drug effects and physical dependence. Second, these experiments will expand the conditions under which discrimination procedures can be used to study dependence by establishing a flumazenil discrimination in monkeys receiving the novel GABAA modulator zolpidem, a drug that is widely prescribed for hypnosis. Third, """"""""blind' drug evaluations will be conducted under the auspices of the CPDD. Collectively, these studies will provide fundamentally new information on the in vivo pharmacology of GABAA modulators and will help to identify the pharmacologic and behavioral determinants of physical dependence on sedative hypnotics.
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