DIVERGENT ALTERATIONS IN GAMMA-AMINOBUTYRIC-ACID RESPONSES OF MALE AND OVARIECTOMIZED RATS AFTER CHRONIC BENZODIAZEPINE AGONIST EXPOSURE - ANALYSIS OF GAMMA-AMINOBUTYRIC ACID-ACTIVATED CHLORIDE INFLUX

Gonadal status in rats modulates the development of tolerance to the a nticonvulsant effects of the benzodiazepines and the concomitant chang es in cortical gamma-aminobutyric acid (GABA)A receptors after chronic benzodiazepine agonist exposure. The present study analyzed physiolog ical GABA responsiveness after chronic benzodiazepine exposure by meas uring GABA-activation of 36chloride influx into cortical and cerebella r microsacs. GABA-stimulated 36chloride influx was compared in groups of male and ovariectomized female rats after acute (2-3 day) or chroni c (3 week) exposure to diazepam-filled or empty silastic implants. Chr onic diazepam exposure increased cortical GABA-activated 36chloride in flux in ovariectomized rats, but did not influence GABA responses in m ales. Acute exposure to diazepam did not alter cortical 36chloride inf lux in either hormone group. Vehicle-treated ovariectomized rats also had lower levels of cortical GABA-activated 36chloride influx than veh icle-treated males. In cerebellar microsacs, diazepam exposure enhance d GABA-induced 36 chloride influx. This effect was observed after both acute and chronic treatments and hormone groups did not differ in the ir response to chronic benzodiazepine exposure. Enhancement of GABA-st imulated 36chloride influx by the benzodiazepine agonist midazolam was not altered in male or ovariectomized rats after chronic diazepam tre atment. Thus, gonad-related factors influence the changes in GABA(A) r eceptors and the resulting GABA responses in the cortex, but not the c erebellum, observed after chronic benzodiazepine agonist exposure in r ats. These regionally specific divergent alterations in GABAergic syst ems may be related to the differential development of tolerance to the anticonvulsant effects of the benzodiazepines observed in these hormo ne groups.