Tolerance and dependence to Δ9-tetrahydrocannabinol in rhesus monkeys: activity assessments
Cannabis withdrawal upon discontinuation of long-term, heavy Cannabis use is reported in humans; however, methods to establish the nature and intensity of cannabinoid withdrawal, especially directly observable signs, have not been widely established. This study quantified activity in the home cage of rhesus monkeys, and examined the extent to which activity can be used to quantify tolerance to and dependence on {Delta}9-tetrahydrocannabinol ({Delta}9-THC). Home-cage activity was measured in one group that received {Delta}9-THC (1 mg/kg s.c.) every 12 h (i.e., chronic {Delta}9-THC), and a second group that received {Delta}9-THC (0.1 mg/kg i.v.) once every 3 days (i.e., intermittent {Delta}9-THC). Treatment was temporarily discontinued in the chronic {Delta}9-THC group and the effects of rimonabant and {Delta}9-THC were examined in both groups. Activity counts were highest during the day (lights on 0600-2000 h) and were lower at night. Rimonabant (0.1-3.2 mg/kg i.v.) dose-dependently increased activity (maximum 20-fold) in the chronic {Delta}9-THC group, but did not significantly alter activity in the intermittent {Delta}9-THC group. {Delta}9-THC (0.32-3.2 mg/kg i.v.) dose-dependently decreased activity counts (maximum 4-fold) in both groups, but was somewhat more potent in the intermittent as compared with the {Delta}9-THC group. Discontinuation of {Delta}9-THC treatment resulted in an immediate (i.e., within 24 h) and time-related increase in activity. Resumption of {Delta}9-THC treatment (1 mg/kg/12 h) produced hypoactivity that was no longer evident within 9 days of treatment. The time-related increase in home-cage activity upon abrupt discontinuation of chronic {Delta}9-THC treatment, as well as the effects of rimonabant to increase activity in monkeys receiving chronic, but not intermittent, {Delta}9-THC treatment, are consistent with signs of physical dependence on {Delta}9-THC in primates.