Nitrous oxide controls the DCN to VTA dopamine circuit by enhancing AMPA receptor functions during rewarding behavior.
Molecular psychiatry May 13, 2026 Fukang Zhang, Shuyuan Fan, Shiqi Li et al.
Exposure to 60% nitrous oxide (N2O), but not 30%, induced conditioned place preference (CPP) reward behavior in rodents and increased the excitability and glutamatergic transmission of dopamine neurons in the ventral tegmental area (VTA). N2O specifically elevated homocysteine levels in the deep cerebellar nuclei (DCN), but blocking homocysteine production did not reduce the rewarding behavior or glutamatergic transmission. Instead, N2O directly enhanced AMPA receptor-mediated glutamatergic transmission and increased activity in both DCN and VTA dopamine neurons. Inhibiting the DCN-VTA circuit via optogenetic long-term depression or chemogenetic inhibition of VTA dopamine neurons reduced N2O-induced CPP. Attenuating N2O-induced potentiation of the DCN-VTA circuit may offer a therapeutic strategy for N2O-related reward behavior.