Repeated administration of phytocannabinoid Δ9-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner

摘要: These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance ∆(9)-THC synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects cellular changes concomitant with their repeated administration mice. Dose-effect relationships for hypothermic were determined order to confirm that SCBs JWH-018 JWH-073 are higher agonists than Separate groups mice treated saline, sub-maximal doses or (3.0mg/kg 10.0mg/kg, respectively) a maximally dose 30.0mg/kg once per day 5 consecutive days while core temperature locomotor activity monitored via biotelemetry. Repeated all resulted tolerance effects, but not this was still evident 14 after last drug administration. Further 4 days, then tested on 5. Mice history cross-tolerant both SCBs, cross-tolerance also persisted testing. Select brain regions from chronically examined CB1 receptor expression function. Expression function hypothalamic CB1Rs reduced receiving chronic drugs, cortical CB1R altered. Collectively, these data demonstrate ∆(9)-THC, can induce long-lasting some which is likely mediated region-specific downregulation desensitization CB1Rs.