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Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem\u2010reward circuitry using a cocaine\u2010induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30\u2010minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non\u2010stressed rats. Intra\u2010laterodorsal tegmental nucleus (LDT) microinjection of a \u03b2 or \u03b12 adrenoceptor antagonist attenuated the stress\u2010induced enhancement of cocaine CPP. Consistent with this observation, intra\u2010LDT microinjection of a \u03b2 or \u03b12 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra\u2010ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress\u2010induced enhancement of cocaine CPP. Finally, intra\u2010medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress\u2010induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine\u2010induced reward value.<\/jats:p>","DOI":"10.1111\/adb.12617","type":"journal-article","created":{"date-parts":[[2018,2,26]],"date-time":"2018-02-26T10:18:04Z","timestamp":1519640284000},"page":"509-521","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Stress augments the rewarding memory of cocaine via the activation of brainstem\u2010reward circuitry"],"prefix":"10.1111","volume":"24","author":[{"given":"Fumiya","family":"Shinohara","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Graduate School of Pharmaceutical Sciences Hokkaido University  Sapporo 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