α₂-Adrenergic receptor modulates 5-HT_2A-mediated behavioral effects of MDMA and psilocybin in mice

Classic serotonergic psychedelics such as psilocybin act as agonists at cortical serotonin (5-HT) 2A receptors (5-HT_2AR), inducing psychedelic effects in humans and head-twitch responses (HTRs) in rodents. Another class of psychedelic drugs called entactogens, exemplified by MDMA, function primarily as monoamine releasers and typically evoke minimal HTR despite causing serotonin release. The polypharmacology of psychedelic drugs at receptors other than 5-HT_2AR may modulate their behavioral effects. Here, we report that MDMA, but not psilocybin, induces robust elevations of both 5-HT and norepinephrine (NE) in the medial prefrontal cortex. Blocking the release of extracellular NE unmasks MDMA-evoked HTR, suggesting that polypharmacology involving noradrenergic receptors may oppose the 5-HT_2A-mediated effects of MDMA. Artificially elevating NE also attenuates psilocybin-induced HTR, supporting this hypothesis. Selective agonism of the noradrenergic α₂ receptor (α₂R) is sufficient to suppress 5-HT_2A-mediated HTR, and also suppresses the HTR in locus coeruleus-ablated mice, suggesting that this effect is mediated by heteroreceptors. Moreover, psilocybin-induced effects in the forced swim test persisted in the presence of α₂R activation. Thus, these findings support a model in which some forms of 5-HT_2A signaling can be attenuated by α₂R activation without interfering with antidepressant-like effects. The ability to reduce potential side effects of 5-HT_2A activation while preserving antidepressant-like effects via α₂R and other analogous receptors may be relevant to therapeutic development.