Divergent alterations in gamma-aminobutyric acid/benzodiazepine responses of male and ovariectomized rats after chronic benzodiazepine agonist exposure: electrophysiological analysis of substantia nigra pars reticulata neurons.
Gonadal status in rats modulates both the apparent development of tolerance to the anticonvulsant effects of the benzodiazepines and the concomitant changes in cortical gamma-aminobutyric acid (GABA)A receptors and GABA-activated 36chloride flux after chronic exposure to a benzodiazepine agonist. By using single-unit electrophysiological techniques, the present study demonstrates disparate neural adaptations in the substantia nigra pars reticulata (SNr) of anesthetized male and ovariectomized (OVX) rats after chronic (3 week) exposure to a benzodiazepine agonist. Unlike males, no reduction in SNr responsiveness to systemically administered diazepam was seen in OVX females after chronic treatment with diazepam-filled implants. In addition, OVX females did not show the compensatory increase in spontaneous firing rate observed in males upon administration of the specific benzodiazepine antagonist, RO15-1788. Sensitivities to locally (microiontophoretically) applied GABA, benzodiazepine agonist (midazolam) and GABA antagonist (SR95531) were not affected by hormone-related factors or chronic exposure to diazepam-filled implants. These results indicate that male and OVX rats show divergent alterations in SNr responses to systemic administration of benzodiazepines after chronic benzodiazepine treatment which appear unrelated to intrinsic changes in responsiveness of the GABA/benzodiazepine receptor complex.
Wilson
M A
MA
Department of Pharmacology, University of South Carolina School of Medicine, Columbia.
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D010052:Ovariectomy; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D012737:Sex Factors; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid