Inhibition of striatal‐enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption. (27th March 2014)

• Record Type: Journal Article
• Authors: Darcq, Emmanuel; Hamida, Sami Ben; Wu, Su; Phamluong, Khanky; Kharazia, Viktor; Xu, Jian; Lombroso, Paul; Ron, Dorit
• Is Part Of: Journal of neurochemistry. Volume 129:Number 6(2014:Jun.)
• Page Start: 1024
• Page End: 1034
• Publication Date: 2014-03-27
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12701
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12701-abs-0001"> <title>Abstract</title> <p>The STriatal‐Enriched protein tyrosine Phosphatase 61 (STEP<sub>61</sub>) inhibits the activity of the tyrosine kinase Fyn and dephosphorylates the GluN2B subunit of the NMDA receptor, whereas the protein kinase A phosphorylation of STEP<sub>61</sub> inhibits the activity of the phosphatase (Pharmacol. Rev.<italic>, </italic><bold>64, </bold><xref ref-type="link" rid="jnc12701-bib-0009">2012</xref>, p. 65). Previously, we found that ethanol activates Fyn in the dorsomedial striatum (DMS) leading to GluN2B phosphorylation, which, in turn, underlies the development of ethanol intake (<italic>J. Neurosci., </italic><bold>30, </bold><xref ref-type="link" rid="jnc12701-bib-0012">2010</xref>, p. 10187). Here, we tested the hypothesis that inhibition of STEP<sub>61</sub> by ethanol is upstream of Fyn/GluN2B. We show that exposure of mice to ethanol increased STEP<sub>61</sub> phosphorylation in the DMS, which was maintained after withdrawal and was not observed in other striatal regions. Specific knockdown of STEP<sub>61</sub> in the DMS of mice enhanced ethanol‐mediated 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 STEP<sub>61</sub> activity in response to ethanol is sufficient for the activation of the Fyn/GluN2B pathway in the DMS. Being upstream of Fyn and GluN2B, inactive STEP<sub>61</sub> in the DMS primes the induction of ethanol intake. <boxed-text content-type="graphic" id="jnc12701-blkfxd-0001" position="anchor" orientation="portrait"><graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pghmh3p2c2" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /></boxed-text></p> <p>We show that ethanol‐mediated inhibition of STEP<sub>61</sub> in the DMS leads to Fyn activation and GluN2B phosphorylation. (a) Under basal conditions, active STEP<sub>61</sub> inhibits Fyn activity and dephosphorylates GluN2B. (b) Ethanol leads to the phosphorylation of STEP<sub>61</sub> on a specific inhibitory site. The inhibition of STEP<sub>61</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.</p> </abstract>