Psychedelics as treatment of alcohol use disorders: insights from preclinical models and comparison of the different psychedelics psilocybin, LSD and ketamine
Résumé
The use of psychedelics to treat alcohol use disorders (AUDs) is very promising, but the mechanisms of action remain poorly understood. We combined behavioral, pharmacological, and gene expression analyses to decipher the mechanisms of action of psilocybin, LSD and ketamine in different animal models of AUDs. Male Long Evans rats underwent chronic operant ethanol self-administration before testing the effect of intraperitoneal psilocybin or LSD, or different enantiomers of ketamine. Psilocybin or LSD were also directly injected within the nucleus accumbens core or other brain regions. Transcripts from the dopaminergic or neuroplasticity pathways were quantified in the nucleus accumbens and prefrontal cortex. Psilocybin or LSD significantly reduced (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 intralateral nucleus accumbens injection of 0.3 μg of the 5-HT2AR antagonist ketanserin. In rats that self-administered ethanol but not in those self-administering saccharin, dopamine D2 receptor mRNAs were increased in both the nucleus accumbens and the prefrontal cortex by psilocybin, while D1R mRNA was increased only in the prefrontal cortex. Regarding ketamine enantiomers, we found specific effects depending on sex and depending on the enantiomers. As in humans, psilocybin reduced ethanol self-administration in rats through the 5-HT2AR within the left nucleus accumbens possibly through increased D2R expression. Our results open unexpected perspectives regarding the hemispheric lateralization of psychedelic effects.
