This FIRST award utilizes well-documented techniques to investigate the role of corticotropin-releasing factor (CRF) neurons in both the therapeutic actions of benzodiazepines as well as the physiological effects associated with abrupt discontinuation of benzodiazepines. In the last decade considerable evidence from a number of investigators using different experimental approaches has accrued consistent with the hypothesis that CRF mediates the endocrine, behavioral and autonomic responses of mammals to stress. Based upon previous preclinical studies which revealed that exposure to stress and treatment with anxiolytic benzodiazepines produce opposite effects on CRF neurons, this proposal seeks to characterize the dose-response effects of various drugs which are active at the benzodiazepine receptor including agonists, partial agonists, antagonists and inverse agonists for their actions on CRF neurons after both acute and chronic administration. In addition, because benzodiazepine withdrawal is associated with physiological symptoms reminiscent of a classic """"""""stress response"""""""", this proposal will seek to investigate whether CRF neurons are involved in the acute drug withdrawal phase. Can intermittent administration of the benzodiazepine antagonist flumazenil during chronic benzodiazepine treatment attenuate drug withdrawal via effects on CRF neurons? Finally, does central administration of a CRF antagonist modify the drug withdrawal phase by altering CRF neuronal activity as measured neurochemically or behaviorally? Currently, the best estimates of CRF neuronal activity are concurrent measurement of CRF concentrations, CRF mRNA expression, and CRF receptor binding in discrete brain regions previously implicated in mediating the actions of CRF. Additional measures of hypothalamic CRF activity will be obtained by measuring plasma ACTH and corticosterone concentrations. These studies will provide further information on the role(s) of CRF in the CNS, and in particular the role of CRF in potentially mediating a portion of the therapeutic (anxiolytic) and deleterious (drug withdrawal) actions of benzodiazepines. Such studies have important implications for the development of novel treatments for anxiety disorders as well as the development of novel agents to ameliorate drug withdrawal symptoms.
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