Chronic benzodiazepine administration. VI. A partial agonist produces behavioral effects without tolerance or receptor alterations.

Chronic benzodiazepine administration has been reported to lead to behavioral tolerance and, in some cases, downregulation of gamma-aminobutyric acid A (GABAA)-receptor binding and function. So-called "partial agonist" benzodiazepines appear to cause limited benzodiazepine effects and little or no behavioral tolerance. To evaluate behavioral and neurochemical effects of a partial agonist during chronic administration, we treated mice with Ro16-6028, 0.25, 1 and 4 mg/kg/day by implanted osmotic pumps, evaluating open-field activity and binding and function at the GABAA receptor. All three doses of Ro16-6028 caused dose-dependent decreases in vertical movements (rearing), and no tolerance was observed up to 14 days at any dose. In contrast, tolerance occurred to the effects of clonazepam at 7 days. Benzodiazepine receptor occupancy was essentially complete in all brain regions evaluated at doses of 1 and 4 mg/kg/day. Benzodiazepine binding in vivo at 0.25 mg/kg/day was transiently decreased in cortex at 7 days but was unchanged in any other brain region. Benzodiazepine binding in cortex in vitro was unchanged over time at any of the three doses, as were t-butylbicyclophosphorothionate binding and binding at the low- and high-affinity GABA sites measured by [3H]SR-95531. GABAA receptor function as determined by muscimol-stimulated chloride uptake was unchanged over 14 days of administration at Ro16-6028 doses of 0.25 and 4 mg/kg/day. Concentrations of Ro16-6028 were constant during administration at 1 and 4 mg/kg/day. These data indicate that chronic Ro16-6028 causes dose-dependent behavioral effects without the development of tolerance and that, despite substantial or complete benzodiazepine receptor occupancy, few effects occur at the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)