Adenylyl Cyclase 1 Is Required for Ethanol-Induced Locomotor Sensitization and Associated Increases in NMDA Receptor Phosphorylation and Function in the Dorsal Medial Striatum.

Autor:	Bosse KE; Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.F.O., C.R.F.)., Oginsky MF; Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.F.O., C.R.F.)., Susick LL; Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.F.O., C.R.F.)., Ramalingam S; Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.F.O., C.R.F.)., Ferrario CR; Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.F.O., C.R.F.)., Conti AC; Research & Development, John D. Dingell VA Medical Center, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan (K.E.B., L.L.S., S.R., A.C.C.); and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.F.O., C.R.F.) alana.conti@wayne.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2017 Nov; Vol. 363 (2), pp. 148-155. Date of Electronic Publication: 2017 Aug 24.
DOI:	10.1124/jpet.117.242321
Abstrakt:	Neuroadaptive responses to chronic ethanol, such as behavioral sensitization, are associated with N -methyl-D-aspartate receptor (NMDAR) recruitment. Ethanol enhances GluN2B-containing NMDAR function and phosphorylation (Tyr-1472) of the GluN2B-NMDAR subunit in the dorsal medial striatum (DMS) through a protein kinase A (PKA)-dependent pathway. Ethanol-induced phosphorylation of PKA substrates is partially mediated by calcium-stimulated adenylyl cyclase 1 (AC1), which is enriched in the dorsal striatum. As such, AC1 is poised as an upstream modulator of ethanol-induced DMS neuroadaptations that promote drug responding, and thus represents a therapeutic target. Our hypothesis is that loss of AC1 activity will prevent ethanol-induced locomotor sensitization and associated DMS GluN2B-NMDAR adaptations. We evaluated AC1's contribution to ethanol-evoked locomotor responses and DMS GluN2B-NMDAR phosphorylation and function using AC1 knockout (AC1KO) mice. Results were mechanistically validated with the AC1 inhibitor, NB001. Acute ethanol (2.0 g/kg) locomotor responses in AC1KO and wild-type (WT) mice pretreated with NB001 (10 mg/kg) were comparable to WT ethanol controls. However, repeated ethanol treatment (10 days, 2.5 g/kg) failed to produce sensitization in AC1KO or NB001 pretreated mice, as observed in WT ethanol controls, following challenge exposure (2.0 g/kg). Repeated exposure to ethanol in the sensitization procedure significantly increased pTyr-1472 GluN2B levels and GluN2B-containing NMDAR transmission in the DMS of WT mice. Loss of AC1 signaling impaired ethanol-induced increases in DMS pGluN2B levels and NMDAR-mediated transmission. Together, these data support a critical and specific role for AC1 in striatal signaling that mediates ethanol-induced behavioral sensitization, and identify GluN2B-containing NMDARs as an important AC1 target. Competing Interests: The authors declare no competing conflict of interest. (Copyright © 2017 by The Author(s).)
Databáze:	MEDLINE
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