TOLERANCE, CROSS-TOLERANCE AND DEPENDENCE MEASURED BY OPERANT RESPONDING IN RATS TREATED WITH TRIAZOLAM VIA OSMOTIC PUMPS

Previous research has found that drugs with affinity for omega (benzodiazepine) sites differ in their abilities to produce tolerance and dependence. The present study therefore investigated the effects of ligands of omega (BZ) sites in rats that had been rendered tolerant to a benzodiazepine. Two experiments were carried out in separate groups of rats. Behavioral changes induced by chronic infusion of triazolam (3 mg/kg/day, SC, for 14 days) via osmotic pumps were studied in animals trained on a fixed ratio 10 schedule of food presentation. Control animals were implanted with pumps containing the vehicle. Test drugs were administered IP using cumulative dosing. In one experiment triazolam decreased response rates on days 1, 2 and 3 after implantation of the pumps and tolerance developed to this depressant effect. In the other experiment, vehicle and triazolam treated rats differed in their responding during chronic infusion but differences were not statistically significant on any particular day. Flumazenil (3.0-30 mg/kg) greatly decreased rates of responding on day 11 in triazolam treated rats. This effect may represent a precipitated withdrawal syndrome. However, no withdrawal effects on operant performance were observed upon pump removal. Chronic infusion of triazolam did not affect the sensitivity of rats to alpidem on day 11 (10-100 mg/kg) whereas it abolished the stimulant effect of bretazenil (0.1-1.0 mg/kg). Chronic triazolam treatment produced tolerance to the depressant effects of triazolam (1.0-3.0 mg/kg), lorazepam (0.3-3.0 mg/kg) and zopiclone (10 mg/kg) but no tolerance to those of CL 218,872 (3.0-30 mg/kg) and zolpidem (0.3-3.0 mg/kg) when tested 3-14 days after pump removal. Differences between compounds highlighted with this model are in agreement with previous observations that these agents possess different pharmacological profiles and different potentials to induce tolerance and dependence.