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However, the precise mechanisms underlying METH withdrawal symptoms remain unknown. Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), have a role the in pathophysiology of depression. In this study, we examined the role of BDNF\u2013TrkB signaling in different brain regions of male mice with METH withdrawal symptoms. Repeated METH (3\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup> per day for 5 days) administration to mice caused a long-lasting depression-like behavior including anhedonia. Western blot analysis showed that BDNF levels in the nucleus accumbens (NAc) of METH-treated mice were significantly higher than those of control mice whereas BDNF levels in other regions, including the prefrontal cortex and hippocampus, were not altered. METH-induced depression-like behavior, behavioral sensitization and dendritic changes in the NAc shell were improved by subsequent subchronic administration of TrkB antagonist ANA-12 (0.5\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup> per day for 14 days), but not TrkB agonist 7,8-dihydroxyflavone (10\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup> per day for 14 days). <jats:italic>In vivo<\/jats:italic> microdialysis showed that METH (1\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>)-induced dopamine release in NAc shell of METH-treated mice was attenuated after subsequent subchronic ANA-12 administration. Interestingly, a single bilateral infusion of ANA-12 into the NAc shell, but not NAc core, showed a rapid and long-lasting therapeutic effect. However, ketamine and paroxetine had no effect. These findings suggest that increased BDNF\u2013TrkB signaling in the NAc shell has an important role in the behavioral abnormalities after withdrawal from repeated METH administration, and that TrkB antagonists are potential therapeutic drugs for withdrawal symptoms in METH abusers.<\/jats:p>","DOI":"10.1038\/tp.2015.157","type":"journal-article","created":{"date-parts":[[2015,10,27]],"date-time":"2015-10-27T17:09:17Z","timestamp":1445965757000},"page":"e666-e666","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["BDNF\u2013TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2982-8824","authenticated-orcid":false,"given":"Q","family":"Ren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J-C","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,27]]},"reference":[{"key":"BFtp2015157_CR1","first-page":"1","volume-title":"New Research on Methamphetamine Abuse","author":"K Hashimoto","year":"2007","unstructured":"Hashimoto K . 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KH has served as a scientific consultant to Astellas, Dainippon-Sumitomo and Taisho, and he has also received research support from Abbvie, Dainippon-Sumitomo, Mochida, Otsuka and Taisho. The remaining authors declare no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}