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<p>Nitrous oxide (N<sub>2</sub>O) is a frequently used recreational drug with significant addictive potential. The ventral tegmental area (VTA) is a key brain region associated with the rewarding effects of drugs of abuse. However, how N<sub>2</sub>O influences VTA functions to mediate reward-related behavior remains poorly understood. We reported that exposure to 60% N<sub>2</sub>O, but not 30%, effectively induced conditioned place preference (CPP) reward behavior and simultaneously increased the excitability and glutamatergic transmission of VTA dopamine neurons. Furthermore, we depicted upstream brain regions that send&#xa0;afferent inputs to the VTA and observed that N<sub>2</sub>O specifically elevated homocysteine levels in the deep cerebellar nuclei (DCN). Interestingly, pharmacological inhibition of homocysteine production did not significantly reduce N<sub>2</sub>O-induced rewarding behavior or the glutamatergic transmission to VTA neurons. Instead, despite being an NMDA receptor antagonist, N<sub>2</sub>O directly enhanced the AMPA receptor-mediated glutamatergic transmission and functionally increased the activity of both DCN and VTA dopamine neurons. Both the optogenetic induction of long-term depression (LTD) in the DCN-VTA neural circuit and the chemogenetic inhibition of VTA dopamine neurons attenuated N<sub>2</sub>O-induced CPP. Taken together, our findings suggest that attenuating N<sub>2</sub>O-induced potentiation of the DCN-VTA circuit may provide a novel therapeutic strategy for treating N<sub>2</sub>O-related reward behavior.</p><p></p>

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Nitrous oxide controls the DCN to VTA dopamine circuit by enhancing AMPA receptor functions during rewarding behavior

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Fukang Zhang,
  • Shuyuan Fan,
  • Shiqi Li,
  • Yixin Xu,
  • Yuxu Ren,
  • Yujing Wang,
  • Xuan Liu,
  • Wei Ma,
  • Jianchen Zhang,
  • Feng Ding,
  • Fangyuan Yin,
  • Li Zhou,
  • Shanwu Feng,
  • Jie Sun,
  • Tengfei Ma

摘要

Nitrous oxide (N2O) is a frequently used recreational drug with significant addictive potential. The ventral tegmental area (VTA) is a key brain region associated with the rewarding effects of drugs of abuse. However, how N2O influences VTA functions to mediate reward-related behavior remains poorly understood. We reported that exposure to 60% N2O, but not 30%, effectively induced conditioned place preference (CPP) reward behavior and simultaneously increased the excitability and glutamatergic transmission of VTA dopamine neurons. Furthermore, we depicted upstream brain regions that send afferent inputs to the VTA and observed that N2O specifically elevated homocysteine levels in the deep cerebellar nuclei (DCN). Interestingly, pharmacological inhibition of homocysteine production did not significantly reduce N2O-induced rewarding behavior or the glutamatergic transmission to VTA neurons. Instead, despite being an NMDA receptor antagonist, N2O directly enhanced the AMPA receptor-mediated glutamatergic transmission and functionally increased the activity of both DCN and VTA dopamine neurons. Both the optogenetic induction of long-term depression (LTD) in the DCN-VTA neural circuit and the chemogenetic inhibition of VTA dopamine neurons attenuated N2O-induced CPP. Taken together, our findings suggest that attenuating N2O-induced potentiation of the DCN-VTA circuit may provide a novel therapeutic strategy for treating N2O-related reward behavior.