Modulation of tolerance to the GABAA agonist THIP by environmental cues.

The present experiment assessed the extent to which environmental stimulation could influence tolerance to the sedative and catatonic effects of the GABAA agonist, 4,5,6,7-tetrahydroisoxozolo(5,4-c)pyridin-3-ol (THIP), through associative learning processes. A conditioning paradigm was used, with THIP as unconditioned stimulus and environmental cues as conditioned stimulus. One group of mice received 15 mg/kg THIP in the testing environment; the second group was exposed to THIP in the colony room, while a third group received only saline. On a tolerance testing session, all mice received 15 mg/kg THIP in the testing environment. Results show that mice previously given THIP in the testing environment display a greater tolerance than mice receiving the drug in the alternative environment. Subsequently, a placebo was given to all mice in the testing environment to assess the influence of environmental cues alone; mice previously given THIP in the testing environment exhibited an enhancement of motility. The results agree with an associative model of tolerance which predicts that environmental cues associated with drug exposure elicit a conditioned compensatory response that cancels the unconditioned effect of the drug.