GABA ENDOCRINE INTERACTIONS IN BENZODIAZEPINE TOLERANCE

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The benzodiazepines (BZs) are widely prescribed drugs, useful for their anxiolytic, anticonvulsant, sedative and muscular relaxant properties. However, the clinical usefulness of the benzodiazepines is hampered by the development of tolerance to their actions during prolonged exposure. This RSDA will enhance the candidate's technical capabilities to analyze neural changes associated benzodiazepine tolerance from the level of gene expression through alterations in neuronal activity of distinct brain loci in freely moving animals. A reduction in formal teaching and service obligations will facilitate the development of new research skills by the candidate, including 1) molecular approaches initiated with in situ hybridization studies, and 2) electrophysiological analysis of neuronal activity in awake, freely moving animals. Since the acute administration of benzodiazepines facilitates the inhibitory effects of gamma-aminobutyric acid (GABA) on neuronal activity, studies examining the neural adaptations underlying the development of benzodiazepine tolerance will focus on GABAergic systems. Both gonadal hormones and stress have been shown to modulate the GABA/benzodiazepine system, including the apparent development of tolerance to the anticonvulsant effects of the benzodiazepines and the concomitant neural GABAergic adaptations following chronic exposure to benzodiazepines in rats. These gonad-related differences in GABA/BZ responses may be related to the dramatic sex differences in hormonal responses to stress in rodents. The proposed experiments will characterize the role of sexually dimorphic stress reactions in mediating gonadal influences on GABA/BZ receptors and their responses in rats, including the GABAergic adaptations associated with chronic benzodiazepine exposure. Studies will investigate the mechanisms through which stress modulates the GABA/BZ system. These studies will determine if a) the sexually dimorphic, stress-induced release of peripheral hormones or b) the central activation of corticotropin releasing factor (CFR) mediate the stress-induced changes in GABA/BZ responses. A second goal is to determine if stress modulates physiological responses to GABA and benzodiazepines in several brain areas of male and female rats using 1) biochemical analysis of GABA- activated chloride influx, 2) electrophysiological determination of neuronal sensitivity to GABA and the benzodiazepines in brain slices, and 3) analysis of fluctuations in neuronal activity in awake rats. Finally, we will assess the interaction between stress and gonadal factors in determining the adaptations associated with chronic benzodiazepine exposure and the associated development of benzodiazepine tolerance in rats. These studies should help elucidate the neural changes associated with tolerance to the benzodiazepines and indicate neural systems which might underlie gender-related influences on the etiology of anxiety or epileptic disorders. The institutional faculty and technological resources make this an ideal site for the candidate to begin molecular investigations of neuronal changes associated with hormones and benzodiazepine exposure using state-of-the-art anatomical resolution, and to ultimately assess the impact of these molecular alterations on neuronal activity in defined brain sites of freely moving animals.