Discriminative Stimulus Properties of Psilocybin and Substituted Tryptamines on Mesolimbic Area

초록

Substance Use Disorder (SUD) remains a critical and increasingly prevalent global health issue, shaped by complex interactions among biological, psychological, and environmental factors. Tryptamines, a class of hallucinogenic compounds structurally related to serotonin, have gained increasing attention due to their psychoactive properties and increasing presence in illicit drug markets. Although compounds such as psilocybin are generally regarded as having low addictive potential, repeated use may still result in compulsive, reward-driven behaviors. Despite their rising use, the precise impact of tryptamines on the brain’s reward circuitry remains inadequately understood. To explore the behavioral and neurobiological effects of psilocybin and its synthetic analogs, we examined the discriminative stimulus properties of psilocybin in mice and evaluated the substitution potential of synthetic tryptamines, including 4-OH-MET, 5-MeO-2-TMT, and 4-Aco-DALT. We further assessed their influence on neural activity and neurotransmitter release in the nucleus accumbens (NAc), with a focus on the underlying neuronal and astrocytic mechanisms. The psilocybin cue fully or partially generalized to the tested synthetic tryptamines. Systemic administration of psilocybin and its analogs significantly decreased GABA release while increasing neuronal firing rates in the NAc. Immunocytochemical analyses further revealed that psilocybin modulates GABA release primarily through astrocytic, rather than neuronal, mechanisms. Taken together, these findings suggest that psilocybin and its synthetic analogs alter NAc activity by decreasing GABAergic transmission and promoting neuronal excitability, predominantly via astrocyte-mediated mechanisms.