Work

Serotonin 2A receptors in the medial prefrontal cortex do not drive DOI-induced head-twitch responses in rodents

Year: 2026

Type: preprint

Abstract: Background The head-twitch response (HTR) is a serotonin 2A receptor (5-HT 2A R) dependent behavioral correlate of serotonergic psychedelic action in rodent models. Although cortical 5-HT 2A Rs have been implicated in HTRs, the contribution of specific cortical circuits to this behavior remains poorly defined, with a few reports implicating the medial prefrontal cortex (mPFC) in the generation of HTRs. Results The serotonergic psychedelic, 2,5-dimethoxy-4-iodoamphetamine (DOI), induced head-twitch responses (HTRs) in male and female rats and mice, with sex differences noted only in mice. DOI also increased ear-scratch responses (ESRs), and reduced digging and grooming behaviors only in mice. While the DOI-evoked HTRs and ESRs were absent in 5-HT 2A R knock-out (5-HT 2A R KO) mice, reduced digging and grooming occurred in both wild-type and 5-HT 2A R KO mice. We assessed the role of 5-HT 2A Rs in the mPFC in regulating DOI-induced HTRs using pharmacological and genetic approaches. Targeted DOI microinfusion into the mPFC did not induce HTRs in rats, in contrast to the robust increase in HTRs noted following systemic DOI administration. Local delivery of the selective 5-HT 2A R antagonist, MDL100907, into the mPFC also had no effect on the systemic DOI-evoked increase in HTRs in rats. Experiments capitalizing on genetic strategies to perturb 5-HT 2A R expression in the mPFC, indicated that viral restoration of 5-HT 2A R expression in mPFC CaMKII-positive excitatory neurons was not sufficient to reinstate DOI-evoked HTRs or ESRs in 5-HT 2A R KO mice. Further, conditional 5-HT 2A R deletion in CaMKII-positive excitatory neurons in the mPFC did not alter systemic DOI-induced HTRs and ESRs in mice. Conclusions These findings indicate that the serotonergic psychedelic DOI induces species- and sex-specific behavioral effects in rodent models, with a robust 5-HT 2A R dependence noted for DOI-evoked HTRs and ESRs. Further, we show that 5-HT 2A Rs in the mPFC do not appear to contribute to the enhanced HTRs and ESRs elicited by DOI.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.05.756681