Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder

Abstract

Preliminary clinical findings, supported by preclinical studies employing behavioral paradigms such as marble burying, suggest that psilocybin may be effective in treating obsessive-compulsive disorder. However, the receptor mechanisms implicated in the putative anti-obsessional effect are not clear. On this background, we set out to explore (1) the role of serotonin 2A (5-HT2A) and serotonin 1A (5-HT1A) receptors in the effect of psilocybin on marble burying; (2) the effect of staggered versus bolus psilocybin administration and persistence of the effect; (3) the effect of the 5-HT1A partial agonist, buspirone, on marble-burying and the head twitch response (HTR) induced by psilocybin, a rodent correlate of psychedelic effects. Male ICR mice were administered psilocybin 4.4 mg/kg, escitalopram 5 mg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) 2 mg/kg, M100907 2 mg/kg, buspirone 5 mg/kg, WAY100635 2 mg/kg or combinations, intraperitoneally, and were tested on the marble burying test. HTR was examined in a magnetometer-based assay. The results show that (1) Psilocybin and escitalopram significantly reduced marble burying. The effect of psilocybin was not attenuated by the 5-HT2A antagonist, M100907. The 5-HT1A agonist, 8-OH-DPAT, reduced marble burying as did the 5-HT1A partial agonist, buspirone. The effect of 8-OH-DPAT was additive to that of psilocybin, but that of buspirone was not. The 5-HT1A antagonist, WAY100635, attenuated the effect of 8-OH-DPAT and buspirone but not the effect of psilocybin. (2) Psilocybin injections over 3.5 h had no effect on marble burying and the effect of bolus injection was not persistent. (3) Co-administration of buspirone with psilocybin blocked its effect on HTR. These data suggest that neither 5-HT2A nor 5-HT1A receptors are pivotally implicated in the effect of psilocybin on marble burying. Co-administration with buspirone may block the psychedelic effects of psilocybin without impeding its anti-obsessional effects.

Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors

“…at a volume of 10 mL/kg. Methods for drug preparation and doses of psilocybin (0.5, 1, or 2 mg/kg), WAY100635 (2 mg/kg), and MDL100907 (1 mg/kg) were chosen based on prior work 33–35 .…”

A dual-receptor model of serotonergic psychedelics

“…Despite the fact that the 5-HT1a agonism of psilocybin does not induce stimulus control, there is still evidence for the role it plays in the drug's behavioral effects, specifically with respect to the modulation of attentional control (Carter et al, 2005), compulsive behavior (Singh et al, 2023), and exploration (Halberstadt et al, 2011). The later study demonstrated that 5-HT1a agonism is likewise primarily implicated in the behavioral and phenomenological effects of 5-MeO-DMT, which is unsurprising, given the high ratio of 5-HT1a…”

Human pluripotent stem cells as a translational toolkit in psychedelic research in vitro

“…Intriguingly, a 5-HT1AR antagonist reversed the drop in body temperature observed in mice after administration of psilocybin, whereas an agonist inhibited some psilocybin-induced effects in humans. 26 , 96 It is crucial to accurately differentiate between pre- and postsynaptic receptors, particularly 5-HT1AR, to capture the cellular and molecular mechanisms governing their efficacy in alleviating disease-related phenotypes associated with presynaptic 5-HT synthesis, reuptake, and release or post-synaptic structural plasticity changes related to the disease.…”