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Rev.<jats:italic>, <\/jats:italic><jats:bold>64,<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#jnc12701-bib-0009\"\/>, p. 65). Previously, we found that ethanol activates Fyn in the dorsomedial striatum (<jats:styled-content style=\"fixed-case\">DMS<\/jats:styled-content>) leading to GluN2B phosphorylation, which, in turn, underlies the development of ethanol intake (<jats:italic>J. Neurosci., <\/jats:italic><jats:bold>30,<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#jnc12701-bib-0012\"\/>, p. 10187). Here, we tested the hypothesis that inhibition of <jats:styled-content style=\"fixed-case\">STEP<\/jats:styled-content><jats:sub>61<\/jats:sub> by ethanol is upstream of Fyn\/GluN2B. We show that exposure of mice to ethanol increased <jats:styled-content style=\"fixed-case\">STEP<\/jats:styled-content><jats:sub>61<\/jats:sub> phosphorylation in the <jats:styled-content style=\"fixed-case\">DMS<\/jats:styled-content>, which was maintained after withdrawal and was not observed in other striatal regions. Specific knockdown of <jats:styled-content style=\"fixed-case\">STEP<\/jats:styled-content><jats:sub>61<\/jats:sub> in the <jats:styled-content style=\"fixed-case\">DMS<\/jats:styled-content> of mice enhanced ethanol\u2010mediated Fyn activation and GluN2B phosphorylation, and increased ethanol intake without altering the level of water, saccharine, quinine consumption or spontaneous locomotor activity. Together, our data suggest that blockade of <jats:styled-content style=\"fixed-case\">STEP<\/jats:styled-content><jats:sub>61<\/jats:sub> activity in response to ethanol is sufficient for the activation of the Fyn\/GluN2B pathway in the <jats:styled-content style=\"fixed-case\">DMS<\/jats:styled-content>. Being upstream of Fyn and GluN2B, inactive <jats:styled-content style=\"fixed-case\">STEP<\/jats:styled-content><jats:sub>61<\/jats:sub> in the <jats:styled-content style=\"fixed-case\">DMS<\/jats:styled-content> primes the induction of ethanol intake.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12701-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>We show that ethanol\u2010mediated inhibition of STEP<jats:sub>61<\/jats:sub> in the DMS leads to Fyn activation and GluN2B phosphorylation. (a) Under basal conditions, active STEP<jats:sub>61<\/jats:sub> inhibits Fyn activity and dephosphorylates GluN2B. (b) Ethanol leads to the phosphorylation of STEP<jats:sub>61<\/jats:sub> on a specific inhibitory site. The inhibition of STEP<jats:sub>61<\/jats:sub> activity contributes to the activation of Fyn in response to ethanol, which, in turn, phosphorylates GluN2B. These molecular adaptations in the DMS promote ethanol drinking.<\/jats:p>","DOI":"10.1111\/jnc.12701","type":"journal-article","created":{"date-parts":[[2014,3,3]],"date-time":"2014-03-03T11:46:21Z","timestamp":1393847181000},"page":"1024-1034","source":"Crossref","is-referenced-by-count":25,"title":["Inhibition of striatal\u2010enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption"],"prefix":"10.1111","volume":"129","author":[{"given":"Emmanuel","family":"Darcq","sequence":"first","affiliation":[{"name":"The Gallo Research Center University of California San Francisco San Francisco California USA"},{"name":"Department of Neurology University of California San Francisco San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sami Ben","family":"Hamida","sequence":"additional","affiliation":[{"name":"The Gallo Research Center University of California San Francisco San Francisco California 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