CONTRIBUTION OF 5-HT2AR TO THE ANTI-ANHEDONIC AND NEUROPLASTICITY EFFECTS OF PSYCHEDELICS
Authors: Horinokita *Ichiro , Koike Hiroyuki , Suzuki Mikio , Futamura Takashi 
Published: February 2025

Abstract

Background
Recently, serotonergic psychedelics have attracted clinical and preclinical attention for their fast-acting and sustained antidepressant effects. Recent studies emphasize the importance of 5- HT2A receptor agonism in the therapeutic effects of psychedelics, as the underlying mechanism for these clinically meaningful improvements is still poorly understood.

Aims
In this study, we used a pharmacological approach to investigate whether 5-HT2AR stimulation is involved in the anti-anhedonic and structural neuroplasticity-inducing effects of the psychedelic drug DOI, a 5-HT2A/2C receptor agonist, and TCB-2, a potent 5-HT2AR agonist, in mouse and rat primary cortical neurons, respectively.

Methods
We treated C57BL/6J mice with corticosterone to induce anhedonia, observed as reduced sucrose preference. To evaluate anti-anhedonic effects of DOI and TCB-2, we injected mice intraperitoneally with them 24 hours before the test. A 5-HT2AR antagonist volinanserin was subcutaneously administrated 10 min before the 5-HT2AR agonist injection. Primary cortical neurons from embryos of female SD rats were cultured and used for assessing effects of 5-HT2AR agonists on neurite length. The necessity for 5-HT2AR stimulation in the structural plasticity was examined using volinanserin and ketanserin which are selective 5-HT2AR antagonists. Comparisons between two-groups were analyzed by unpaired t-test. Multiple group comparisons were assessed by one-way ANOVA followed by Dunnett’ s post hoc test. A p value less than 0.05 was considered statistically significant.

Results
TCB-2 and DOI improved the chronic corticosterone-induced reduction in sucrose preference in dose-dependent manner. The anti-anhedonic effect of TCB-2 was antagonized by pretreatment with volinanserin. Treatment with DOI and TCB-2 for 48 hours promoted neurite outgrowth in a concentration-dependent manner, and this effect was inhibited by both ketanserin and volinanserin.

Conclusion
We demonstrated that DOI and TCB-2 exerted the antidepressant-like effects after a single injection in a behavioral model of anhedonia and both compounds increased neurite length of rat cortical neurons. The behavioral and structural plasticity effects were dependent on 5-HT2A receptor activation, as indicated by blocking 5-HT2AR using selective 5-HT2AR antagonists. Thus, our findings suggest that 5-HT2AR activation is necessary for the antidepressant and neuroplasticity-inducing effects of psychedelics. Given that traditional antidepressants are effective in the animal model of chronic corticosterone treatment, our findings indicate that the effects of DOI and TCB-2 are rapid onset. Furthermore, since the behavioral effects of DOI and TCB-2 were observed 24 hours after treatment and both compounds promoted structural neuroplasticity in vitro primary culture of cortical neurons, it is likely that such plasticity potentially mediates their antidepressant-like effects. This conclusion is further supported by our findings that 5-HT2A receptor activation is necessary for both behavioral and neuroplasticity effects. Future work leading to a precise delineation of downstream signaling pathway of 5-HT2AR activation by psychedelics and neural circuits responsible for the antidepressant effects is needed to elucidate the mechanisms of action of psychedelics and develop an agent with more beneficial therapeutic effects.