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 anticonvulsant effects of the benzodiazepines and the concomitant changes in cortical gamma-aminobutyric acid (GABA)A receptors after chronic benzodiazepine agonist exposure. The present study analyzed physiological GABA responsiveness after chronic benzodiazepine exposure by measuring GABA-activation of 36chloride influx into cortical and cerebellar microsacs. GABA-stimulated 36chloride influx was compared in groups of male and ovariectomized female rats after acute (2-3 day) or chronic (3 week) exposure to diazepam-filled or empty silastic implants. Chronic diazepam exposure increased cortical GABA-activated 36chloride influx in ovariectomized rats, but did not influence GABA responses in males. Acute exposure to diazepam did not alter cortical 36chloride influx in either hormone group. Vehicle-treated ovariectomized rats also had lower levels of cortical GABA-activated 36chloride influx than vehicle-treated males. In cerebellar microsacs, diazepam exposure enhanced GABA-induced 36chloride influx. This effect was observed after both acute and chronic treatments and hormone groups did not differ in their response to chronic benzodiazepine exposure. Enhancement of GABA-stimulated 36chloride influx by the benzodiazepine agonist midazolam was not altered in male or ovariectomized rats after chronic diazepam treatment. Thus, gonad-related factors influence the changes in GABAA receptors and the resulting GABA responses in the cortex, but not the cerebellum, observed after chronic benzodiazepine agonist exposure in rats. These regionally specific divergent alterations in GABAergic systems may be related to the differential development of tolerance to the anticonvulsant effects of the benzodiazepines observed in these hormone groups.
Department of Pharmacology, University of South Carolina School of Medicine, Columbia.
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MA
Wilson
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Biscardi
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D010052:Ovariectomy; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D012737:Sex Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D002712:Chlorides; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; D008874:Midazolam