Cannabinoid-induced lower lip retraction in rats

Rationale Lower lip retraction (LLR) in rats has been described as a distinctive effect of 5-HT 1A agonists. In the course of evaluating behavioral effects of cannabinoid agonists in rats, LLR effects were evident following injection of several cannabinoid agonists. Objectives To pharmacologically characterize cannabinoid-induced LLR in rats. Methods Lower lip retraction was scored using a 3-point scale for up to 6 h after injection of the cannabinoid agonists Δ 9 -tetrahydrocannabinol (Δ 9 -THC, 1–10 mg/kg), AM7499 (0.01–1.0 mg/kg), or AM2389 (0.003–0.1 mg/kg), or, for comparison, the 5-HT 1A agonist 8-OH-DPAT (0.01–0.3 mg/kg). Next, antagonist effects of rimonabant (1–10 mg/kg) and WAY100635 (0.3 mg/kg) on LLR produced by cannabinoid or 5-HT 1A agonists were evaluated. Lastly, effects of 8-OH-DPAT were determined following pretreatment with AM2389 (0.003–0.01 mg/kg) or Δ 9 -THC (1 mg/kg). Results All three cannabinoid agonists produced LLR. Effects of AM2389 were attenuated by both rimonabant and WAY100635 whereas effects of 8-OH-DPAT were antagonized by WAY 100635 but not by rimonabant. Pretreatment with 1 mg/kg Δ 9 -THC or 0.01 mg/kg AM2389 shifted the 8-OH-DPAT dose-effect function for LLR to the left and isobolographic analysis of the data indicates CB1 and 5-HT 1A interactions can be supraadditive. Conclusions Cannabinoid agonists produce LLR in rats, an effect heretofore ascribed only to activity at 5-HT 1A receptors, via CB1 receptor-mediated actions. Co-administration of a cannabinoid agonist and the 5-HT 1A agonist 8-OH-DPAT results in a synergistic effect on LLR.