Conditioned tolerance to haloperidol- and droperidol-induced catalepsy

Summary

The possible mechanisms of conditioned tolerance to the cataleptogenic effects of haloperidol and droperidol were studied in order to discriminate between “classical” and “conditioned” tolerance. Rats were conditioned by repeated administration (19–27 times) of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i. p.), respectively, in the presence of a sum of defined environmental (auditory, olfactory and tactile) stimuli. The animals were compared with pseudoconditioned rats, which underwent the same number of drug injections and exposures to the environmental stimuli, but neither were associated. In part of the experiments, one further group of rats was repeatedly treated with only solvent in the presence of the environmental stimuli. Rats conditioned with haloperidol or droperidol showed tolerance to the cataleptogenic effect of a test dose of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i.p.), respectively, when they were tested in presence of the defined conditioning stimuli. The rats conditioned with droperidol showed significantly less catalepsy than the pseudoconditioned animals 30 min after droperidol administration, whereas in rats conditioned with haloperidol, the catalepsy was less pronounced no sooner than 120 min after haloperidol administration. This was a manifestation of conditioned tolerance. In rats pseudoconditioned with droperidol, the catalepsy was similar to that produced by the drug in drug-naive rats, suggesting no classical tolerance due to repeated administration of the neuroleptic drug. The dopamine turnover in striatum or nucleus accumbens after administration of 1.5 mg/kg of haloperidol i.p. was not altered in rats conditioned with haloperidol when compared with pseudoconditioned animals. The stereotypies produced by apomorphine (0.16 mg/kg s. c.) were most pronounced in conditioned, less pronounced in pseudoconditioned and very small in drug-naive rats. These result suggest that the conditioned tolerance to the neuroleptic drugs is connected with an increased sensitivity of the basal ganglia to dopaminergic drugs. In another series of experiments, rats were conditioned with apomorphine 8 times and tested with 0.66 mg/kg of droperidol i.p. Rather unexpectedly, the catalepsy was significantly more pronounced in conditioned than in pseudoconditioned animals. This observation suggests that the type of conditioned effect, which becomes manifest, depends in part on the drug used in the presence of the conditioned stimuli.