Associative influences on tolerance to decreased fixed-interval responding by clonidine

Responding of rats was maintained under a 5-min fixed-interval schedule of food presentation. One group of animals (n = 5) received the alpha-2-agonist clonidine (0.1 mg/kg/day) before experimental sessions for 16 weeks. Additional animals (n = 5) also received 0.1 mg/kg/day for 16 weeks but experienced drug administration after sessions for 4 weeks, before sessions for 4 weeks, after sessions for 4 weeks, and then finally, before sessions for 4 weeks. Animals receiving clonidine before daily experimental sessions for the entire period developed tolerance to decreased responding within 3 weeks, and their responding remained near control levels except when clonidine was occasionally preceded by the alpha-2-antagonist yohimbine. Animals receiving clonidine after sessions did not develop tolerance, and responding was markedly suppressed during the first exposure to presession clonidine. When these animals subsequently received clonidine again after sessions, responding was disrupted (increased) in spite of continued drug administration as if animals were "dependent" on clonidine in specific circumstances. When these animals again received clonidine before sessions, responding was partially suppressed in spite of uninterrupted drug administration as if animals had "lost" tolerance in specific circumstances. Tolerance to the behavioral effects of clonidine on fixed-interval responding was not determined by the presence of drug alone, but by the associative influence of drug-related effects in the presence of specific environmental stimuli.