Rationale: Recently, Δ9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and synthetic cannabinoid receptor agonists reportedly reduced the head-twitches induced by the 5-HT 2A/2C receptor agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI) in mice, which is mediated via the activation of 5-HT 2A receptor. However, the effect of endogenous cannabinoid anandamide on the head-twitch response has not been studied. Objectives: In this study, we investigated the effect of anandamide on the DOI-induced head-twitch response in mice. Methods: Five minutes after the injection of DOI (5 mg/kg IP), the number of head-twitches was counted for a 5-min period. THC or anandamide was injected IP 60 min or 10 min before the number of head-twitches was counted, respectively. Results: THC and anandamide each reduced the DOI-induced head-twitch response. The inhibition of the DOI-induced head-twitch response by THC was reversed by SR141716A (N-piperidino-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide), a CB 1 receptor antagonist, while the effect of anandamide was not blocked by SR141716A. Cyclooxygenase (COX) inhibitors such as aspirin and indomethacin reversed the inhibition of the DOI-induced head-twitch response by anandamide. On the other hand, COX inhibitors did not affect the inhibition of the DOI-induced head-twitch response by THC. Conclusions: Taken together, these findings suggest that the endocannabinoid anandamide may inhibit 5-HT 2A receptor-mediated function via the arachidonic acid cascade, but not via a direct interaction with the CB1 cannabinoid receptor, and that the mechanism of its action is clearly different from that of THC.
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