Psilocybin reduces alcohol self-administration via selective left nucleus accumbens activation in rats

Psilocybin reduces alcohol self-administration in rats by 50% when injected 4 hours before a drinking session, either intraperitoneally (1 mg/kg) or directly into the left nucleus accumbens (0.15 μg), but not the right nucleus accumbens or left ventral tegmental area. The effect is blocked by a 5-HT2A receptor antagonist injected into the left nucleus accumbens. Psilocybin increases dopamine D2 receptor mRNA in the nucleus accumbens and prefrontal cortex of rats that self-administered alcohol, but not saccharin, and increases D1 receptor mRNA only in the prefrontal cortex. These findings suggest psilocybin acts through the 5-HT2A receptor in the left nucleus accumbens, potentially via increased D2 receptor expression, and reveal unexpected hemispheric lateralization of psychedelic effects.

Study at a glance

Abstract

Abstract The use of psilocybin to treat alcohol use disorder is very promising, but its mechanisms of action remain poorly understood. We combined behavioural, pharmacological and gene expression analyses to decipher the mechanisms of action of psilocybin, for the first time, when injected into the brain. Male Long Evans rats underwent chronic operant ethanol self-administration before testing the effect of intraperitoneal psilocybin or directly within the nucleus accumbens core or the ventral tegmental area. Transcripts from the dopaminergic system were quantified in the nucleus accumbens and prefrontal cortex. Psilocybin significantly reduced (by 50%) ethanol self-administration when injected 4 h before the session either intraperitoneally (1 mg/kg) or directly within the left nucleus accumbens (0.15 μg) but not the right nucleus accumbens or the left ventral tegmental area. The effect of intraperitoneal injection of psilocybin was prevented by intra-left nucleus accumbens injection of 0.3 μg of the 5-HT2A receptor antagonist ketanserin. In rats that self-administered ethanol but not in those self-administering saccharin, dopamine D2 receptor (D2R) mRNA was increased in both the nucleus accumbens and the prefrontal cortex by psilocybin, while dopamine D1 receptor mRNA was increased only in the prefrontal cortex. As in humans, psilocybin reduced ethanol self-administration in rats through the 5-HT2A receptor within the left nucleus accumbens, possibly through increased D2R expression. Our results open unexpected perspectives regarding the hemispheric lateralization of psychedelic effects.