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Previously, we reported that orexins released during stress, via orexin OX<jats:sub>1<\/jats:sub> receptors (OX<jats:sub>1<\/jats:sub>Rs), contribute to the reinstatement of cocaine seeking through endocannabinoid\/CB<jats:sub>1<\/jats:sub> receptor (CB<jats:sub>1<\/jats:sub>R)\u2010mediated dopaminergic disinhibition in the ventral tegmental area (VTA). Here, we further demonstrated that NPS released during stress is an up\u2010stream activator of this orexin\u2010endocannabinoid cascade in the VTA, leading to the reinstatement of cocaine seeking. Mice were trained to acquire cocaine conditioned place preference (CPP) by context\u2010pairing cocaine injections followed by the extinction training with context\u2010pairing saline injections. Interestingly, the extinguished cocaine CPP in mice was significantly reinstated by intracerebroventricular injection (<jats:italic>i.c.v<\/jats:italic>.) of NPS (1 nmol) in a manner prevented by intraperitoneal injection (<jats:italic>i.p<\/jats:italic>.) of SHA68 (50 mg\/kg), an NPS receptor antagonist. This NPS\u2010induced cocaine reinstatement was prevented by either <jats:italic>i.p<\/jats:italic>. or intra\u2010VTA microinjection (<jats:italic>i.vta<\/jats:italic>.) of SB\u2010334867 (15 mg\/kg, <jats:italic>i.p<\/jats:italic>. or 15 nmol, <jats:italic>i.vta<\/jats:italic>.) and AM 251 (1.1 mg\/kg, <jats:italic>i.p<\/jats:italic>. or 30 nmol, <jats:italic>i.vta<\/jats:italic>.), antagonists of OX<jats:sub>1<\/jats:sub>Rs and CB<jats:sub>1<\/jats:sub>Rs, respectively. Besides, NPS (1 nmol, <jats:italic>i.c.v<\/jats:italic>.) increased the number of c\u2010Fos\u2010containing orexin neurons in the lateral hypothalamus (LH) and increased orexin\u2010A level in the VTA. The latter effect was blocked by SHA68. Furthermore, a 30\u2010min restraint stress in mice reinstated extinguished cocaine CPP and was prevented by SHA68. These results suggest that NPS is released upon stress and subsequently activates LH orexin neurons to release orexins in the VTA. The released orexins then reinstate extinguished cocaine CPP via an OX<jats:sub>1<\/jats:sub>R\u2010 and endocannabinoid\u2010CB<jats:sub>1<\/jats:sub>R\u2010mediated signaling in the VTA.<\/jats:p>","DOI":"10.1111\/adb.12971","type":"journal-article","created":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T03:43:00Z","timestamp":1603165380000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Stress induces reinstatement of extinguished cocaine conditioned place preference by a sequential signaling via neuropeptide S, orexin, and endocannabinoid"],"prefix":"10.1111","volume":"26","author":[{"given":"Yu\u2010Hsien","family":"Chou","sequence":"first","affiliation":[{"name":"Graduate Institute of Pharmacology, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia Chun","family":"Hor","sequence":"additional","affiliation":[{"name":"Graduate Institute of Pharmacology, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming Tatt","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute of Pharmacology, College of Medicine National Taiwan University  Taipei Taiwan"},{"name":"Graduate Institute of Brain and Mind Sciences, College of Medicine National Taiwan University  Taipei Taiwan"},{"name":"Faculty of Pharmaceutical Sciences UCSI University  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsin\u2010Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute of Pharmacology, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Remo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Department 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