Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development.

This study compared the potency and efficacy of the cannabinoids delta-tetrahydrocannabinol (delta-THC), HU-210, WIN 55,212-2 and CP 55,940 in suppressing food-reinforced operant behavior, increasing reaction latency in a hot-plate test and inducing hypothermia, and tested whether these behavioral effects induced by CP 55,940 showed differential sensitivity to the cannabinoid CB1 receptor antagonist SR141716A, and to tolerance development. After acute i.p. administration to rats, operant behavior was more potently affected than reaction latency and body temperature, but the order of potency of the different drugs was similar across the tests: HU-210<CP 55,940<WIN 55,212-2=delta-THC. SR141716A blocked the hypothermic and analgesic effects more potently/efficiently than the response-rate suppressive effect of CP 55,940. After repeated administration of CP 55,940, the extent and speed of tolerance development was most pronounced in the hypothermia test, and least pronounced in the operant test. It is concluded that the more the behavioral effect induced by a cannabinoid receptor agonist is situated at the left-hand side of the dose-spectrum, the more the effect is resistant to blockade by a cannabinoid receptor antagonist and to the development of tolerance. The possible consequence of this observation for the therapeutic use of cannabinoids is discussed.