title: Protein tyrosine phosphatase α in the dorsomedial striatum promotes excessive ethanol-drinking behaviors.
abstract: We previously found that excessive ethanol drinking activates Fyn in the dorsomedial striatum (DMS) (Wang et al., 2010; Gibb et al., 2011). Ethanol-mediated Fyn activation in the DMS leads to the phosphorylation of the GluN2B subunit of the NMDA receptor, to the enhancement of the channel's activity, and to the development and/or maintenance of ethanol drinking behaviors (Wang et al., 2007, 2010). Protein tyrosine phosphatase α (PTPα) is essential for Fyn kinase activation (Bhandari et al., 1998), and we showed that ethanol-mediated Fyn activation is facilitated by the recruitment of PTPα to synaptic membranes, the compartment where Fyn resides (Gibb et al., 2011). Here we tested the hypothesis that PTPα in the DMS is part of the Fyn/GluN2B pathway and is thus a major contributor to the neuroadaptations underlying excessive ethanol intake behaviors. We found that RNA interference (RNAi)-mediated PTPα knockdown in the DMS reduces excessive ethanol intake and preference in rodents. Importantly, no alterations in water, saccharine/sucrose, or quinine intake were observed. Furthermore, downregulation of PTPα in the DMS of mice significantly reduces ethanol-mediated Fyn activation, GluN2B phosphorylation, and ethanol withdrawal-induced long-term facilitation of NMDAR activity without altering the intrinsic features of DMS neurons. Together, these results position PTPα upstream of Fyn within the DMS and demonstrate the important contribution of the phosphatase to the maladaptive synaptic changes that lead to excessive ethanol intake.
authors.affiliation: Gallo Center at the Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Ben Hamida
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Darcq
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Su
authors.initials: S
authors.lastname: Wu
authors.forename: Khanhky
authors.initials: K
authors.lastname: Phamluong
authors.forename: Viktor
authors.initials: V
authors.lastname: Kharazia
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000222:Adaptation, Physiological; D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D051076:Proto-Oncogene Proteins c-fyn; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4