Lysergic acid diethylamide (LSD) promotes social behaviour through 5-HT 2A 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.