Psilocybin sex-dependently reduces alcohol consumption in C57BL/6J mice

Abstract

The classical psychedelic psilocybin is of interest as a treatment for alcohol use disorder (AUD). This study investigated the effects of psilocybin on voluntary ethanol consumption in adult male and female C57BL/6J mice administered saline or psilocybin intraperitoneally as a single dose of 0.1, 0.5, 1.0 or 2.0 mg/kg and provided 20% ethanol utilizing a two-bottle choice alcohol drinking paradigm. Ethanol was provided continuously for 3 days immediately following the administration of psilocybin, then withheld for 2 days, and then provided continuously for two subsequent additional days. A multilevel model (MLM) for repeated measures was used to compare ethanol consumption and preference in psilocybin-treated groups versus controls. Ethanol consumption and preference were reduced in male mice during the 3-day interval that immediately followed psilocybin administration. The effect of psilocybin on ethanol consumption was dose-related and was consistent across the 3-day interval at dosages of 0.5 mg/kg or greater. Psilocybin had no effect on consumption or preference when ethanol was subsequently reintroduced after 2 days of withdrawal. In contrast to males, psilocybin had no significant effect on ethanol consumption or preference in female mice at any dosage or time point. The lack of an effect of psilocybin on quinine preference, and its limited interaction with locomotor activity indicated that the observed reduction in voluntary ethanol consumption was not attributable to altered taste perception or motor effects. Total fluid consumption was increased in males at some time points and psilocybin dosages and unchanged in females, and the absence of any decrease in either group at any time point indicated that the observed reduction in ethanol consumption was not mediated by nonspecific effects on consummatory behavior. The finding of a sex-dependent effect of psilocybin on ethanol consumption suggests that the C57BL/6J mouse may provide a useful experimental approach to modeling sex differences in vulnerability to AUD in addition to investigation of the neurobiological basis of the effect of classical psychedelics on alcohol drinking behavior.

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats

“…The 0.1 mg/kg dose is categorized as a microdose, given that it is one-tenth of the minimum dose required for eliciting behavioral and cellular effects in rats 18,44 . The 1 mg/kg dose is among the most extensively studied doses in rodents for both behavioral and molecular effects [44][45][46] , while 3 mg/kg falls within the range of therapeutic doses for humans 18 . RM-ANOVA analysis revealed no main effect of psilocybin treatment or psilocybin by time interactions for any dose of psilocybin compared to vehicle for either lever presses or infusions (Figure 1G, H).…”

“…Lack of efficacy from the 1.0 mg/kg psilocybin dose on heroin relapse may be due to the fact that occupancy of 5-HT 2A R is estimated to only be ~30% with 1.0 mg/kg IP dosages 62 . The 1 mg/kg dose is among the most extensively studied doses in rodents for both behavioral and molecular effects [44][45][46] , while 3 mg/kg falls within the range of therapeutic doses for humans 18 . While psilocybin does induce head-twitch responses in rodents, the 3 mg/kg dose has been reported to induce less head-twitch responses compared to the 1 mg/kg dose over time but 3 mg/kg induces a rapid, short-lived head-twitch response in rodents that may be further indicative of unique molecular and behavioral consequences that arise from the two doses 39,40 .…”

“…While these exciting findings demonstrate psilocybin reduces heroin relapse, limitations of the study include use of only male animals, given that sex-specific effects of psilocybin on mouse ethanol drinking 46 and responses to 5-HT 2A R psychedelics have been reported 89–91 . In our initial investigation, we employed a subchronic treatment with high doses of psilocybin, an approach that may lack translational validity, to enable direct comparisons with both the microdosing protocol and the ketanserin antagonist treatment.…”

Chemogenetic Perturbation of the Posterior But Not Anterior Cerebellum Reduces Voluntary Ethanol Consumption

“…Various rodent models of alcohol exposure and consumption have shown sex-specific differences in the amounts of alcohol consumed, aversion resistance, alcohol seeking behaviors, magnitude and direction of alcohol-induced neuronal activity changes, and brain neuronal network adaptations ( Fulenwider et al, 2019 ; Xie et al, 2019 ; Nimitvilai et al, 2020 ; Alper et al, 2022 ; Leyrer-Jackson et al, 2022 ; Foo et al, 2023 ; Nimitvilai-Roberts et al, 2023 ; Sneddon et al, 2023 ). These differences are likely because of distinct neurophysiology and brain connectivity in males versus females.…”

Acute but not long-lasting antidepressant-like effect of psilocybin in differential reinforcement of low-rate 72 schedule in rats

“…Similarly, Shao et al (2021) reported an immediate antidepressant-like effect of acute treatment with psilocybin (1 mg/kg), displayed as a reduced number of failed escapes in the mouse learned-helplessness test. Alper et al (2023) recently demonstrated that psilocybin (0.1–2 mg/kg) reduced alcohol consumption in mice. Single psilocybin injection (0.05–0.1 mg/kg) produced also a pro-motivational effect in the progressive ratio schedule in rats (Higgins et al, 2021).…”