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Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell.
Mangieri, Regina A; Maier, Esther Y; Buske, Tavanna R; Lasek, Amy W; Morrisett, Richard A.
Afiliación
  • Mangieri RA; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, AustinTX, United States.
  • Maier EY; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, AustinTX, United States.
  • Buske TR; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, AustinTX, United States.
  • Lasek AW; Department of Psychiatry, University of Illinois at Chicago, ChicagoIL, United States.
  • Morrisett RA; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, AustinTX, United States.
Front Pharmacol ; 8: 533, 2017.
Article en En | MEDLINE | ID: mdl-28860990
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase recently implicated in biochemical, physiological, and behavioral responses to ethanol. Thus, manipulation of ALK signaling may represent a novel approach to treating alcohol use disorder (AUD). Ethanol induces adaptations in glutamatergic synapses onto nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs), and putative targets for treating AUD may be validated for further development by assessing how their manipulation modulates accumbal glutamatergic synaptic transmission and plasticity. Here, we report that Alk knockout (AlkKO) mice consumed greater doses of ethanol, relative to wild-type (AlkWT) mice, in an operant self-administration model. Using ex vivo electrophysiology to examine excitatory synaptic transmission and plasticity at NAcSh MSNs that express dopamine D1 receptors (D1MSNs), we found that the amplitude of spontaneous excitatory post-synaptic currents (EPSCs) in NAcSh D1MSNs was elevated in AlkKO mice and in the presence of an ALK inhibitor, TAE684. Furthermore, when ALK was absent or inhibited, glutamatergic synaptic plasticity - long-term depression of evoked EPSCs - in D1MSNs was attenuated. Thus, loss of ALK activity in mice is associated with elevated ethanol consumption and enhanced excitatory transmission in NAcSh D1MSNs. These findings add to the mounting evidence of a relationship between excitatory synaptic transmission onto NAcSh D1MSNs and ethanol consumption, point toward ALK as one important molecular mediator of this interaction, and further validate ALK as a target for therapeutic intervention in the treatment of AUD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Pharmacol Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Pharmacol Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza