The intensity of head-twitch and the 5-HT syndrome (tremor, fore-paw treading, head-weaving, hind-limb abduction) was measured in male CFLP mice after injection of 5 mg/kg 5-MeODMT. Head-twitch showed a clear circadian variation, with highest scores mid-light, but no circadian variation in the 5-HT syndrome was observed. Dose-response curves for 5-MeODMT (2-64 mg/kg) confirmed the head-twitch difference, with a parallel rightward shift for mid-dark versus mid-light up to 32 mg/kg, while no difference appeared for the 5-HT syndrome. Time-course measurements showed no differences between mid-light and mid-dark, making pharmacokinetic explanations unlikely. The circadian rhythm in head-twitch but not in the 5-HT syndrome suggests these behaviors are mediated by different 5-HT receptor subtypes.
Four benzodiazepines (diazepam, clonazepam, oxazepam, and clobazam) potentiated head-twitch responses in mice induced by directly acting serotonin receptor agonists (5-MeODMT, quipazine, mescaline) but not by the indirectly acting agonist 5-HTP, which was sometimes inhibited. The potentiation of 5-MeODMT by clonazepam (10 mg/kg) was not blocked by flumazenil, bicuculline, or serotonin depletion, nor mimicked by muscimol (which inhibited head-twitches). These findings suggest the potentiation occurs postsynaptically and is not mediated by benzodiazepine receptors. Failure to potentiate 5-HTP responses likely results from reduced serotonin neuronal activity via benzodiazepine receptors, since co-administration of flumazenil and clonazepam potentiated 5-HTP effects while each alone had no effect.