Lysergic acid diethylamide (LSD) promotes social behaviour through 5-HT2A and ampa in the medial prefrontal cortex (MPFC)

Introduction Autism Spectrum Disorder and Social Anxiety Disorder are mental illnesses characterized by a dysfunction in social behavior (SB); a phenomenon largely mediated by the medial prefrontal cortex (mPFC). Clinical studies have demonstrated that lysergic acid diethylamide (LSD), a partial agonist of the 5-HT 2A receptor, can promote SB. However, its mechanism of action on SB is unknown. Objectives To assess the effects of repeated LSD administration on social behavior in mice and to identify which mPFC receptors mediate LSD’s behavioral effects. Methods Eight-week-old C57BL/6J male mice received vehicle or repeated LSD (30 μg/kg/day i.p. for 7 days) as well the selective 5-HT 2A receptor antagonist MDL, or the AMPA receptor antagonist NBQX. Twenty-four hours following the last injection, mice underwent the Direct Social Interaction Test and the Three-Chamber Test (TCT) to assess sociability and preference for social novelty. in vivo electrophysiological recordings were performed in mice treated with vehicle or LSD using multi-barrelled electrodes for microiontophoretic ejections of the selective 5-HT 2A receptor agonist DOI or the selective AMPA receptor agonist quisqualate on mPFC pyramidal neurons. Results Repeated treatment with low doses of LSD increased the interaction time in the DSI as well as sociability and social novelty indices in the TCT. These pro-social effects were blocked by the intra-PFC administration of both 5-HT 2A and AMPA antagonists. LSD also potentiated, in a current-dependent manner, the excitatory response of mPFC neurons to 5-HT 2A and AMPA agonists. Conclusions Repeated, low doses of LSD increases social behavior via a mechanism of action that is mediated by 5-HT 2A and AMPA in the mPFC.