HORMONES, GABA RESPONSES, AND BENZODIAZEPINE TOLERANCE

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The benzodiazepines (BZs) are widely prescribed drugs, useful for their anxiolytic, anticonvulsant, sedative and muscle relaxant properties. However, the clinical usefulness of the benzodiazepines is hampered by the development of tolerance to their actions during prolonged exposure. 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 have focused on GABAergic systems. Both gonadal hormones and stress have been shown to modulate the: GABA/benzodiazepine system. In rats, in vivo fluctuations in gonadal hormones modulate GABAergic systems, but not the acute anticonvulsant actions of the benzodiazepines. However, gonadal status does modify both 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 (CRF) mediate the stress-induced changes in GABA/BZ responses. A second goal is to determine if stress modulates neuronal responses to GABA and/or the benzodiazepines in a sexually dimorphic manner. Physiological responses to GABA and benzodiazepines will be measured in several brain areas of male and female rats using l) 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, freely moving 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.