Enhanced dopamine transporter binding is associated with species-specific 2C-B-induced reinforcement in marmosets, but not in mice

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Hallucinogens have been prescribed for the treatment of mental illnesses; however, reports on the dependence potential of hallucinogens across species remain inconsistent. Non-human primate (NHP) self-administration model are suitable for evaluating species-specific reinforcement behavior induced by hallucinogens. In this study, we demonstrated that 4-bromo-2,5-dimethoxyphenethylamine (2C-B) was self-administered orally in freely moving marmoset (Callithrix jacchus). 2C-B-treated mice did not demonstrate reinforcement behavior in self-administration paradigm as well as brain stimulation behavior in intracranial self-stimulation (ICSS) test. Interestingly, 2C-B-induced dopamine neuronal activity was demonstrated only in the brain of marmosets as evidenced by fluorescent false neurotransmitter assessment and measurement of synaptosome dopamine levels. We sought to study possible molecular mechanisms underlying this and docking simulations revealed that 2C-B occupied a binding pocket overlapping the canonical dopamine-binding site in both species but adopted a distinct interaction pattern in marmoset DAT involving Leu321. Pull-down assays demonstrated stronger DAT-associated 2C-B binding in marmosets than in mice. Furthermore, 2C-B produced greater inhibition of DAT-mediated FFN102 uptake in cells expressing marmoset or human DAT than in cells expressing mouse DAT, whereas substitution of Leu321 abolished this effect. Collectively, these findings demonstrate that 2C-B induces reward-related behaviors in marmosets and identify species-specific DAT-2C-B interactions as a potential mechanism underlying differential dopaminergic and behavioral responses across species.