Nitrous Oxide, A Classic Anesthetic, Exerts Addictive Effects via Regulating D1 Receptor and BDNF Pathway in Ventral Tegmental Area-Nucleus Accumbens Dopamine Circuit

摘要

Recreational use of nitrous oxide(N2O) has increased dramatically in recent decades. This study aimed to examine its addictive properties and the underlying mechanisms. In mice, exposure to a subanesthetic concentration(20%) of N2O for 30 minutes, repeated for 4 consecutive days(paired with a specific context in the morning and air in the afternoon), induced apparent rewarding behavior in the conditioned place preference(CPP) paradigm. This effect was abolished by microinjection of the dopamine(DA) D1 receptor antagonist SCH23390 into the nucleus accumbens(NAc), but not by the D2 antagonist haloperidol. N2O robustly enhanced the activity of dopaminergic neurons in the ventral tegmental area(VTA) and increased DA concentration in the NAc. Repeated N2O exposure also upregulated the expression of brain-derived neurotrophic factor(BDNF) in the VTA and its downstream mediators in the NAc. Conversely, focal knockdown of BDNF in the VTA or inhibition of its downstream mediators suppressed the N2O-induced rewarding effect and VTA dopaminergic neuronal activity. Furthermore, combined intervention with BDNF knockdown and D1 antagonist significantly inhibited the N2O-induced rewarding effect, which was greater than BDNF knockdown alone but not significantly different from D1 antagonist alone. These results indicate that the rewarding properties of N2O at subanesthetic concentration are associated with its upregulation of the VTA-NAc DA reward pathway, likely mediated by the D1 receptor and BDNF/TrkB signaling, with BDNF modulation potentially acting upstream of the D1 receptor.

关键词

nitrous oxide / addictive effects / ventral tegmental area-nucleus accumbens / BDNF / dopamine