A single dose of psilocybin reduces voluntary ethanol consumption in male mice for three days afterward, but has no effect in female mice. The reduction is dose-related and occurs at 0.5 mg/kg or higher, but does not persist when ethanol is reintroduced after two days of withdrawal. The effect is not due to altered taste perception, motor effects, or nonspecific changes in drinking behavior. These findings suggest sex-dependent effects of psilocybin on alcohol drinking and indicate that the C57BL/6J mouse may be useful for studying sex differences in alcohol use disorder and the neurobiology of psychedelics.
A single high dose of LSD (50 μg/kg) reduced alcohol consumption by an average of 17.9% in adult male mice over 46 days, with no change in total fluid intake or activity. A lower dose (25 μg/kg) had no effect. The findings suggest classical hallucinogens warrant further animal research for addiction neurobiology and drug discovery.
Ibogaine, a psychoactive alkaloid from the root bark of Tabernanthe iboga, is used to treat addiction and is a candidate for pharmaceutical development. Its ability to inhibit acetylcholinesterase (AChE) has pharmacological and toxicological relevance. Using Ellman's reagent with physostigmine as a control, ibogaine inhibited AChE with an IC50 of 520 ± 40 μM. This inhibition is physiologically negligible and does not explain functional effects in animals or humans that might suggest involvement of muscarinic acetylcholine pathways.
Dopaminergic hyperactivity in the prefrontal cortex (PFC) may contribute to cognitive dysfunction in schizophrenia. In rats, subchronic treatment with phencyclidine (PCP) at doses of 10 mg/kg/day or higher produced serum concentrations associated with PCP psychosis in humans. PCP-treated rats showed a significant, dose-dependent enhancement in amphetamine-induced dopamine release in the PFC but not in the nucleus accumbens (NAc), along with increased locomotor activity. This enhanced response appeared after 3 days of treatment, persisted through 14 days, and resolved within 4 days of withdrawal. The findings suggest that NMDA receptor dysfunction could underlie the dopaminergic abnormalities seen in schizophrenia and that even short-term PCP abuse may potentiate the effects of psychostimulants.