Pimavanserin, a 5-hydroxytryptamine 2A receptor inverse agonist, reverses prepulse inhibition deficits in the nucleus accumbens and ventral hippocampus.

Prepulse inhibition (PPI) is disrupted in many neuropsychiatric diseases. Although the inverse agonist of the 5-hydroxytryptamine 2A (5-HT2A) receptors, pimavanserin, alleviates PPI deficits in rodents, the precise mechanisms and critical brain areas in the reversal effect of 5-HT2A receptor inverse agonists remain unclear. The present study aimed to investigate the critical brain areas responsible for the reversal effect of the 5-HT2A receptor inverse agonist on PPI deficits in male mice. The results showed that intraperitoneal administration of pimavanserin was found to improve normal PPI behavior and reverse PPI deficits elicited by the dopamine D1/D2 receptor nonselective agonist, pergolide. Further, local infusion of pimavanserin into the nucleus accumbens and ventral hippocampus reversed PPI deficits, whereas the same manipulation in the medial prefrontal cortex or ventral tegmental area did not reverse PPI deficits. Overall, the nucleus accumbens and ventral hippocampus are the critical brain areas responsible for the reversal effect of 5-HT2A inverse agonists on PPI deficits. Such findings contribute to the extensive exploration of the accurate molecular and neural mechanisms underlying the antipsychotic effects of 5-HT2A receptor inverse agonists, especially the neural circuits modulated by 5-HT2A receptor activity.