Chronic administration of a benzodiazepine agonist appears to downregulate benzodiazepine receptors and γ-aminobutyric acid (GABA) receptor function. To examine the effects of chronic treatment with a benzodiazepine antagonist, we administered Ro15-1788, 1, 2 and 5 mg/kg/day to mice via implanted s.c. osmotic pumps for 1 to 14 days. Plasma and cortex (CX) concentrations of Ro15-1788 remained constant between days 1 and 7, indicating no change in pharmacokinetics. Open-field activity studies showed no change in distance traveled or ambulatory time at days 1, 2 and 4, but an increase in both parameters at days 7 and 14 in mice receiving Ro15-1788, 2 mg/kg/day. Benzodiazepine binding was unchanged in CX, cerebellum (CB), hypothalamus, hippocampus and pons-medulla at 1, 2 and 4 days at a dose of 2 mg/kg/day. Binding was increased in CX, CB and hippocampus at day 7 compared to days 1 and 2, and remained elevated at day 14. Similar results were observed at Ro15-1788 doses of 1 and 5 mg/kg/day. Benzodiazepine binding assessed in vitro in CX and CB also was increased at day 7 compared to day 1, due to an increase in receptor number rather than a change in apparent affinity. Binding of t-[35S]butylbicyclophosphorothionate to the chloride channel site in CX after Ro15-1788, 2 mg/kg/day, was increased at days 7 and 14 compared to days 1, 2 and 4 and controls due to an increase in number of binding sites. t-Butylbicyclophosphorothionate binding in CB was unchanged throughout. GABA(A) receptor function as determined by chloride uptake into cortical synaptoneurosomes was increased at day 7 compared to day 1 after Ro15-1788, 2 mg/kg/day. These data indicate that both benzodiazepine and chloride channel sites and GABA(A) receptor function in CX are upregulated after chronic antagonist treatment. Differing results in other brain regions indicate the presence of regionally specific adaptation processes.
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1989|