Is serotonin involved in hypothermic effect and its tolerance development of Δ⁸-tetrahydrocannabinol and 11-hydroxy-Δ⁸-tetrahydrocannabinol in the mouse?

The role of serotonin in the hypothermic effect and its tolerance development of Δ⁸-tetrahydrocannabinol (Δ⁸-THC) and 11-hydroxy-Δ⁸-tetrahydrocannabinol (11-OH-Δ⁸-THC) was investigated in mice. Pretreatment with p-chorophenylalanine (300 mg/kg i.p. for 2 days and 100 mg/kg i.p. for 1 day) or 5,6-dihydroxytryptamine (50 μg/mouse i.c.v) did not block the hypothermic effect of both cannabinoids (5 mg/kg i.v.). Cinanserine, an antagonist for serotonin receptor, was also unable to block the effect of the cannabinoids. On the other hand, both cannabinoids-tolerant mice (5 mg/kg/day i.v. for 3 days) showed partially cross-tolerance to the hypothermic effect of serotonin (160 μg/mouse i.c.v. or 10 mg/kg i.v.). Moreover, daily administration of cinanserine (10 mg/kg i.p.) inhibited partially tolerance development to the hypothermic effect of Δ⁸-TH and 11-OH-Δ⁸-THC. These results suggest that serotonin is not primarily responsible for the hypothermic effect of Δ⁸-THC and 11-OH-Δ⁸-THC but may have some role in the tolerance development to the hypothermic effect of these cannabinoids in mice.