Synergistic inhibition by benzodiazepine and barbiturate drugs of the clock control of ovulation in hamsters.
A surge of pituitary luteinizing hormone (LH) into the bloodstream occurs in hamsters every 4 days between 1:30 p.m. and 3 p.m. in response to a signal from a biological clock. This surge initiates behavioral estrus approximately 2 h later and ovulation approximately 12 h later. Phenobarbital at a dose > or = 100 mg/kg consistently blocks LH release. Barbiturate and benzodiazepine drugs have separate binding sites in the GABAA receptor/chloride channel complex. Binding of either drug increases GABA-mediated chloride conductance, which suppresses the postsynaptic neuron. Barbiturate binding also increases benzodiazepine binding. This suggested that these drugs might synergize to inhibit LH release. A combination of triazolam and phenobarbital at doses of 10 mg/kg injected s.c. at 1:30 p.m. inhibited ovulation and extended the 4-day vaginal cycle in all treated hamsters. Either drug dose injected alone at 1:30 p.m., or the combination at 3 p.m., was completely ineffective. Bicuculline prevented inhibition by the combination at 1:30 p.m. The clock signal for LH release may act by antagonizing GABA transmission, which may be chronically inhibiting LH release. The combination delimited a 75-min period (1:30-2:45 p.m.) within which the clock signal for LH release occurred in all individuals (ET50 = 2:08 p.m.). This period appears to arise from individuals with different but constant clock settings rather than from a 75-min variation in the clock setting of the individual.
Alleva
J J
JJ
Center for Drug Evaluation and Research, Food and Drug Administration, Washington, D.C., USA.
Alleva
F R
FR
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002940:Circadian Rhythm; D006224:Cricetinae; D004357:Drug Synergism; D004971:Estrus / Q000187:drug effects; D005260:Female; D058787:GABA-A Receptor Antagonists; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors; D008647:Mesocricetus; D010060:Ovulation / Q000187:drug effects*; D010634:Phenobarbital / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014229:Triazolam / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D058787:GABA-A Receptor Antagonists; D014229:Triazolam; D007986:Luteinizing Hormone; D001640:Bicuculline; D010634:Phenobarbital