263. NITROUS OXIDE EXERTS REWARDING EFFECT VIA REGULATING D1 RECEPTOR AND BDNF PATHWAY IN VENTRAL TEGMENTAL AREA-NUCLEUS ACCUMBENS DOPAMINE CIRCUIT

Abstract Background Nitrous oxide (N2O), often known as laughing gas, is an inhalational anesthetic and analgesic which use for recreational purpose has risen dramatically worldwide over the past decades. The N2O abuse is particularly serious in adolescents with an estimated prevalence of 2%-15.8%. However, little is known about the underlying mechanisms of such addiction-like rewarding effects. Aims & Objectives This study aimed to examine its rewarding effect and the underlying mechanisms. Method Orthogonal design was applied to optimize the N2O exposure pattern and the rewarding effects of N2O were evaluated in mice in the conditioned place preference (CPP) paradigm. Regional microinjection and focal knockdown in the brain of genetically engineered mice were utilized for optic-fiber recording and monitoring real-time neurochemical effects of N2O exposure. Results The exposure of mice to a subanesthetic concentration (20%) of N2O for 30 min for 4 consecutive days paired with N2O in the morning and paired with the air in the afternoon produced apparent rewarding behavior. This was abrogated by microinjection into the nucleus accumbens (NAc) of the dopamine (DA) D1 receptor antagonist SCH23390, but not the D2 antagonist haloperidol. N2O robustly enhanced DAergic neuronal activity of the ventral tegmental area (VTA) and the concentration of DA in the NAc. The repeated N2O exposure also upregulated the expression of brain-derived neurotrophic factor (BDNF) in the VTA and its multiple downstream mediators in the NAc. Conversely, VTA focal knockdown of BDNF and the inhibition of the downstream mediators suppressed the N2O-induced rewarding effect and the DAergic neuronal activity of the VTA. Further, the combined intervention of BDNF knockdown and D1 antagonist significantly inhibited the N2O-induced rewarding effect in mice, which was greater than that of BDNF knockdown alone, but was not significantly different from that of D1 antagonist alone. Discussion & Conclusions These results indicate that the rewarding properties of N2O at subanesthetic concentration are associated with its upregulation of the VTA-NAc DA reward pathway probably via mediation of D1 receptor and BDNF/TrkB signaling. Among them, the modulation of BDNF may be the upstream of D1 receptor involved in N2O rewarding effect.