Psilocybin reduces alcohol self-administration via selective left nucleus accumbens activation in rats
Brain – May 04, 2024
Source: OpenAlex
Summary
A powerful hallucinogen, psilocybin, drastically reduced alcohol self-administration by 50% in male rats. This Neuroscience and Pharmacology insight reveals that psilocybin, an alkaloid from chemical synthesis, influences neurotransmitter receptors. Specifically, injecting psilocybin (0.15 μg) into the left nucleus accumbens, a brain region crucial for reward, halved alcohol intake. This effect, vital for future Medicine and Psychology applications in Psychedelics and Drug Studies, was mediated by 5-HT2A receptors and increased dopamine D2 receptor mRNA.
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.