The benzodiazepines (BZs) are widely used for their anxiolytic, anticonvulsant, sedative and muscle relaxant properties, although their clinical usefulness is hampered by the development of tolerance to these various pharmacological effects during prolonged exposure. The actions of the benzodiazepines are mediated through binding to a high-affinity recognition site in the brain which alters the responsiveness of the inhibitory neurotransmitter GABA. Recently, several studies have demonstrated that steroid hormones or their derivatives can alter the GABA/BZ/ionophore complex and GABA- mediated responses. The proposed experiments are aimed at more closely examining the interactions between gonadal steroid hormones, the benzodiazepine receptor site and GABA responses in rats. I will examine the effects of gender, castration, hormone replacements and estrous cycle on the benzodiazepine recognition site and GABA modulation of this site. Several brain areas which are thought to mediate benzodiazepine responses and/or are target areas for steroid actions will be analyzed. Further, various hormonal manipulations will be tested for their ability to influence neuronal responses to GABA and/or benzodiazepine administration in rats. Using electrophysiological techniques, these studies will examine hormonal influences on neuronal activity and GABA sensitivity in two brain areas under differing GABAergic control; the substantia nigra pars reticulata and the dorsal raphe nucleus. Hormone effects on GABA responses will be analyzed in vivo and in brain slices to help elucidate the mechanisms by which steroid hormones can influence responses to prolonged benzodiazepine exposure in rats. These studies will examine if manipulating levels of gonadal hormones can alter some of the biochemical and physiological changes in GABAergic responses previously observed in male rats following prolonged benzodiazepine exposure. In addition,the effects of the steroid milieu on prolonged benzodiazepine exposure. In addition, the effects of the steroid milieu on anticonvulsant effects of the benzodiazepines and the development of tolerance to these effects will be studied. Understanding the effects of gonadal steroids on GABAergic systems, on responses to the benzodiazepines and on the development of benzodiazepine tolerance could lead to novel treatment regimens designed to modify certain benzodiazepine actions and/or the development of tolerance to these actions.
