363. DIFFERENTIAL EFFECTS OF PSILOCYBIN AND LISURIDE ON SEROTONIN AND DOPAMINE NEURONAL ACTIVITY AND BEHAVIOR

Psilocybin and lisuride both bind to 5-HT2A receptors, but only psilocybin produces hallucinogenic effects. In adult male mice, both drugs inhibited serotonin neuron activity in the dorsal raphe nucleus and dopamine neuron firing in the substantia nigra. A 5-HT2A antagonist blocked psilocybin's serotonin inhibition but not lisuride's, suggesting different mechanisms. Only lisuride showed an antidepressant-like effect at the highest doses. Psilocybin, but not lisuride, elicited head-twitch responses, and lisuride blocked those induced by psilocybin. Both drugs reduced locomotion. The findings indicate lisuride has antidepressant and sedative effects without hallucinogenic action, likely due to its distinct effects on serotonin and dopamine neurons.

Study at a glance

Abstract

Abstract Background Psychedelics hold potential as therapeutics in psychological disorders. Even if they primarily act on 5-HT2A receptors, their mechanisms and effects on the brain are not well understood. Simply activating 5-HT2A receptors does not induce psychedelic effects. For example, psilocybin and lisuride both bind to 5-HT2A receptors, but only psilocybin induces hallucinogenic effects. Moreover, psilocybin and lisuride may both be effective in treating psychological disorders such as major depressive disorder. Aims & Objectives The goal of this study was to better characterize the differences and similarities between the effects of psilocybin and lisuride on serotonin (5-HT) neurons of the dorsal raphe nucleus, dopamine (DA) neurons of the substantia nigra (SN), and behavioral paradigms of locomotion and depressive-like behavior. Method Adult male C57BL6/N mice received intraperitoneal injections (i.p.) of psilocybin (0.5-3mg/kg) or lisuride (0.1-0.5mg/kg) or vehicle and 5-HT/DA neuron firing activity was recorded until the maximum inhibition was found. Moreover, other mice received i.p. injections of psilocybin (0.3, 1, or 3 mg/kg) or lisuride (0.05, 0.15, or 0.5 mg/kg) and tested in behavioral tests. Briefly, head twitch response was recorded in the first 10 minutes after injection, and then either open field test or forced swim test was conducted 20 minutes after injection. Results Psilocybin and lisuride inhibited 5-HT activity in the DRN (p = 0.0052, p = 0.0326, respectively). Moreover, the 5-HT2A antagonists MDL 100907 prevented the 5-HT inhibition induced by psilocybin, but not by lisuride. Both psilocybin and lisuride decreased the DA firing rate in SN neurons (p = 0.0198, p = 0.0418, respectively). MDL 100907 blocked the effect of lisuride and to a lesser extent of psilocybin. Only lisuride elicited an antidepressant-like effect at the highest doses tested (p = 0.007). Psilocybin, but not lisuride, elicited HTR, and lisuride blocked the psilocybin-induced HTR (p < 0.0001). Both psilocybin and lisuride decreased locomotion in the OFT (p < 0.0001, p = 0.0097, respectively). Discussion & Conclusions These results suggest that lisuride has antidepressant and sedative effects without producing HTR, likely due to its differential action on 5-HT and DA neurons. Lisuride inhibits the serotoninergic system, like psilocybin. However, the actions in which these two drugs use are different, with only psilocybin’s effect at the 5-HT2A receptor. Moreover, both lisuride and psilocybin inhibit the dopaminergic system. Although, our data suggest that while both drugs impact the dopaminergic system via 5-HT2A receptors, this is most prominent for lisuride, as psilocybin was only partially mediated by MDL 100907.