{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T12:36:50Z","timestamp":1786711010755,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004480","name":"Natural Science Foundation of Shanxi Province","doi-asserted-by":"publisher","award":["202403021211125"],"award-info":[{"award-number":["202403021211125"]}],"id":[{"id":"10.13039\/501100004480","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nitrous oxide (N2O), commonly known as laughing gas, is widely used for its anesthetic and analgesic properties in medical settings. However, its recreational abuse has escalated, leading to severe neurological complications including cognitive impairment, yet the underlying mechanisms remain poorly understood. In this study, male C57BL\/6 J mice were exposed to either normal air inhalation or nitrous oxide inhalation for 28 days to evaluate the effects of repeated nitrous oxide exposure on cognitive function. We employed hippocampal transcriptome sequencing, real-time PCR, Western blotting, and non-targeted plasma metabolomics to explore potential regulatory mechanisms. Repeated nitrous oxide exposure impaired motor skills, learning, and cognitive abilities in mice. Integrative multi-omics analysis revealed that differentially expressed metabolites and genes synergistically disrupted energy metabolism through co-regulation of the TCA cycle, MAPK signaling pathway, and pyrimidine metabolism, ultimately leading to impaired cellular signaling, nucleic acid synthesis, and cognitive dysfunction. Our study provides novel multi-omics insights into the MAPK\/ERK\/CREB-mediated neurotoxicity and energy metabolism collapse induced by nitrous oxide as a recreational drug of abuse, offering new directions for clinical intervention.<\/jats:p>","DOI":"10.3390\/molecules31162844","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:57:46Z","timestamp":1786708666000},"page":"2844","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nitrous Oxide as a Recreational Drug of Abuse: Multi-Omics Insights into MAPK\/ERK\/CREB-Mediated Neurotoxicity and Energy Metabolism Collapse"],"prefix":"10.3390","volume":"31","author":[{"given":"Juan","family":"Jia","sequence":"first","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"},{"name":"Shanxi Key Laboratory of Forensic Medicine, Jinzhong 030600, China"},{"name":"Shanxi Province Engineering Research Center of Forensic Identification, Jinzhong 030600, China"},{"name":"Key Laboratory of Forensic Toxicology of Ministry of Public Security, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"},{"name":"Shanxi Key Laboratory of Forensic Medicine, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Nan","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"},{"name":"Shanxi Key Laboratory of Forensic Medicine, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyun","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"},{"name":"Shanxi Key Laboratory of Forensic Medicine, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Xue","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"},{"name":"Shanxi Key Laboratory of Forensic Medicine, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congying","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keming","family":"Yun","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"},{"name":"Shanxi Key Laboratory of Forensic Medicine, Jinzhong 030600, China"},{"name":"Key Laboratory of Forensic Toxicology of Ministry of Public Security, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangwei","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Shanxi Medical University, Jinzhong 030600, China"},{"name":"Shanxi Key Laboratory of Forensic Medicine, Jinzhong 030600, China"},{"name":"Shanxi Province Engineering Research Center of Forensic Identification, Jinzhong 030600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.1111\/bcp.14779","article-title":"Nitrous oxide-induced neurotoxicity: A case report and literature review","volume":"87","author":"Thayabaran","year":"2021","journal-title":"Br. 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