Tolerance development to the effect of delta9-tetrahydrocannabinol on conditioned behavior: role of treatment interval and influence of microsomal metabolism
Davis, W.M.; Borgen, L.A.
Archives Internationales de Pharmacodynamie et de Therapie 213(1): 97-112
1975
ISSN/ISBN: 0003-9780 PMID: 1156021 Document Number: 84592
The importance of frequency of administration in the development of tolerance to delta9-tetrahydrocannabinol (delta9-THC) was studied with repeated administration of the drug prior to behavioral test sessions at 1-, 3-, 7- or 14-day intervals. Partial tolerance was seen to develop to the depressant effects of delta9-THC (10mg/kg i.p.) on food-motivated performance on a variable interval 60-sec (VI 60) schedule of reinforcement. The tolerance was most evident with the most frequent exposure to the drug. No signs of increasing responsiveness to delta9-THC were seen with any of the four inter-injection intervals. The role of hepatic metabolism in tolerance to delta9-THC was tested by pretreating animals with SKF-525A, a microsomal enzyme inhibitor, or phenobarbital, a microsomal enzyme inducer. The dosing schedules for SKF-525A and phenobarbital were sufficient to alter hexobarbital sleeping time significantly, but they did not affect the normal VI 60 sec performance. After a 5 mg/kg dose of SKF-525A the depressant actions of 3 and 10 mg/kg doses of delta9-THC appeared to show a slight but consistent enhancement during the course of tolerance development. Phenobarbital (80 mg/kg/day) pretreatment for seven days blocked the acute behavioral depressant effect of 3 mg/kg of delta9-THC and appeared to enhance the development of tolerance. A metabolic mechanism of tolerance development was suggested by the data, but not demonstrated definitively.