Prefrontal 5-HT _2A receptors directly contribute to tic ontogeny: translational evidence

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics and frequently accompanied by comorbidities such as obsessive-compulsive disorder (OCD) and pathological aggression. Although approved pharmacotherapies often reduce tic severity, they frequently cause adverse effects and are insufficient for managing comorbid symptoms, underscoring the need for improved treatments. Recent evidence indicates that the serotonin 5-HT _2A receptor (5-HT _2A R) antagonist pimavanserin reduces tic severity and improves quality of life, yet its mechanism of action in TS remains unclear. Here, we combine postmortem human and preclinical approaches to gain insight into the role of 5-HT _2A Rs in TS. Western-blot analyses of postmortem prefrontal cortex (PFC) samples obtained from individuals with TS revealed a pronounced, male-specific elevation of 5-HT _2A R protein levels in Brodmann Area (BA) 10. We then tested pimavanserin and the selective 5-HT _2A R antagonist volinanserin in two mouse models of TS: D1CT-7 transgenic mice and mice with early-life depletion of striatal cholinergic interneurons. Systemic administration of pimavanserin (1-2 mg·kg⁻¹, IP) or volinanserin (0.1-0.3 mg·kg⁻¹, IP) robustly reduced tic-like movements and stereotypies in both models. Local infusion of pimavanserin into the medial PFC, but not the dorsal striatum, recapitulated these effects, indicating a cortical locus of action. Pimavanserin also reduced resident-intruder aggression, but not locomotion or anxiety-like behavior. Together, these findings identify elevated prefrontal 5-HT _2A Rs as a key mechanistic contributor to TS and a promising therapeutic target for individuals with TS and pathological aggression.