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Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) display psychomotor abnormalities, most of which are ameliorated by atypical antipsychotics with serotonin (5-HT) 2A receptor (5-HT 2A ) antagonism. Heterozygous  Pacap  mutant mice show a significantly higher hallucinogenic response than wild-type mice to a 5-HT 2A  agonist. Endogenous PACAP may, therefore, affect 5-HT 2A  signaling; however, the underlying neurobiological mechanism for this remains unclear. Here, we examined whether PACAP modulates 5-HT 2A  signaling by addressing cellular protein localization. PACAP induced an increase in internalization of 5-HT 2A  but not 5-HT 1A , 5-HT 2C , dopamine D 2  receptors or metabotropic glutamate receptor 2 in HEK293T cells. This PACAP action was inhibited by protein kinase C inhibitors, β-arrestin2 silencing, the PACAP receptor PAC1 antagonist PACAP 6-38 , and PAC1 silencing. In addition, the levels of endogenous 5-HT 2A  were decreased on the cell surface of primary cultured cortical neurons after PACAP stimulation and were increased in frontal cortex cell membranes of  Pacap −/−    mice. Finally, intracerebroventricular PACAP administration suppressed 5-HT 2A  agonist-induced head twitch responses in mice. These results suggest that PACAP–PAC1 signaling increases 5-HT 2A  internalization resulting in attenuation of 5-HT 2A -mediated signaling, although further study is necessary to determine the relationship between behavioral abnormalities in  Pacap −/−    mice and PACAP-induced 5-HT 2A  internalization.

PACAP–PAC1 Signaling Regulates Serotonin 2A Receptor Internalization