Activity of prefrontal cortex serotonin 2A receptor expressing neurons is necessary for the head-twitch response of mice to psychedelic drug DOI in a sex-dependent manner

Abstract Serotonin 2A receptors (5-HT2ARs) mediate the effects of psychedelic drugs. 5-HT2AR agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT2AR expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT2ARs control the HTR. Here, we use an optogenetic approach to examine whether activation of 5-HT2AR expressing neurons in the mouse prefrontal cortex (PFC) is sufficient to induce HTRs alone, or may augment the HTR produced by DOI, and if inhibition of these neurons prevents DOI-induced HTRs in mice. We crossed Htr2a-Cre mice to Cre-dependent optogenetic lines Ai32 (channelrhodopsin) and Ai39 (halorhodopsin) to selectively activate and inhibit (respectively) 5-HT2AR-expressing neurons in the PFC of adult mice. We found that optogenetic stimulation of PFC 5-HT2AR expressing neurons in the absence of an agonist does not increase HTRs in mice. In both male and female Ai32 mice that received vehicle, there was no difference in HTRs in mice that expressed Htr2a-Cre compared with control mice, indicating that optogenetic activation of 5-HT2AR+ cells in the PFC was not sufficient to produce HTRs in the absence of an agonist. In female mice, activation of PFC 5-HT2AR expressing neurons augmented the HTR produced by DOI. However, this result was not seen in male mice. In contrast, inhibition of 5-HT2AR expressing neurons in the PFC prevented the increase in HTR produced by DOI in male, but not in female, mice. Together, these findings suggest that activation of 5-HT2ARs in the PFC is not sufficient to induce HTRs in the absence of a 5-HT2AR agonist but is necessary for induction of HTRs by a 5-HT2AR agonist in a sex-dependent manner. Competing Interest Statement The authors have declared no competing interest.