A56: Effectiveness of Psilocybin in Females Depends on Estrous Stage

The tryptamine psilocybin exerts its hallucinogenic effects primarily through agonism of 5-HT2A  receptors. 5-HT2A receptor expression fluctuates across the estrous cycle, driven by variation in estradiol level. Therefore, it is likely that the hallucinogenic effects of the drug may also vary across the estrous cycle. The head twitch response, also called wet dog shake, can be used to assess 5-HT2A receptor activation in rodents. Therefore, we studied the ability of psilocybin to induce head twitch responses in females at various stages of their estrous cycle. Psilocybin (1mg/kg) was administered intragastrically to 12 naturally cycling Long Evans females in proestrus or diestrus, with head twitch responses quantified for 30 minutes immediately after. Preliminary results showed that psilocybin administered in the proestrus phase failed to increase head twitch responses, while administration during diestrus produced the expected increase in head twitch responses. Additionally, separate animals placed in an anestrous state (n=12) by subcutaneous injection of 3.5mg medroxyprogesterone acetate 24 hours prior to testing also showed the expected increase in head twitch responses. To determine a potential mechanism for these effects, we conducted a Western Blot analysis of 5-HT2A and 5-HT2C receptor levels in the medial prefrontal cortex during proestrus, diestrus, and in anestrous animals. Activation of 5-HT2C receptors has been previously shown to inhibit the action of 5-HT2A agonists. We found that the balance between these receptors shifts across the estrous cycle, potentially explaining the observed variation in head twitch responses. Recent studies utilizing psilocybin point towards potential therapeutic benefits for serotonin-linked mood disorders common in women, such as Major Depressive Disorder and Premenstrual Dysphoric Disorder. Funding for this research was provided by PsyBio Therapeutics, Inc.

Author(s): Margaret Wilson, Zoology and Neuroscience Major

Aine Powell, Psychology Major

Advisor(s): Matthew McMurray, Department of Psychology

Oscar Sandoval, Department of Psychology