Evidence for Phosphorylation-Dependent, Dynamic, Regulation of mGlu5 and Homer2 in Expression of Cocaine Aversion in Mice.

Autor:	Szumlinski KK; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106 Kimberly.huber@utsouthwestern.edu szumlinski@ucsb.edu.; Department of Molecular, Cellular and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106., Beltran J; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106., van Doren E; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106., Jimenez Chavez CL; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106., Domingo-Gonzalez RD; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106., Reyes CM; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106., Ary AW; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106., Lang A; Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106., Guo W; Department of Neuroscience, O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390., Worley PF; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205., Huber KM; Department of Neuroscience, O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Kimberly.huber@utsouthwestern.edu szumlinski@ucsb.edu.
Jazyk:	angličtina
Zdroj:	ENeuro [eNeuro] 2023 Apr 25; Vol. 10 (4). Date of Electronic Publication: 2023 Apr 25 (Print Publication: 2023).
DOI:	10.1523/ENEURO.0423-22.2023
Abstrakt:	Cocaine-induced changes in the expression of the glutamate-related scaffolding protein Homer2 influence this drug's psychostimulant and rewarding properties. In response to neuronal activity, Homer2 is phosphorylated on S117/S216 by calcium-calmodulin kinase IIα (CaMKIIα), which induces a rapid dissociation of mGlu5-Homer2 scaffolds. Herein, we examined the requirement for Homer2 phosphorylation in cocaine-induced changes in mGlu5-Homer2 coupling, to include behavioral sensitivity to cocaine. For this, mice with alanine point mutations at (S117/216)-Homer2 ( Homer2 AA/AA ) were generated, and we determined their affective, cognitive and sensorimotor phenotypes, as well as cocaine-induced changes in conditioned reward and motor hyperactivity. The Homer2 AA/AA mutation prevented activity-dependent phosphorylation of S216 Homer2 in cortical neurons, but Homer2 AA/AA mice did not differ from wild-type (WT) controls with respect to Morris maze performance, acoustic startle, spontaneous or cocaine-induced locomotion. Homer2 AA/AA mice exhibited signs of hypoanxiety similar to the phenotype of transgenic mice with a deficit in signal-regulated mGluR5 phosphorylation ( Grm5 AA/AA ). However, opposite of Grm5 AA/AA mice, Homer2 AA/AA mice were less sensitive to the aversive properties of high-dose cocaine under both place-conditioning and taste-conditioning procedures. Acute injection with cocaine caused dissociation of mGluR5 and Homer2 in striatal lysates from WT, but not Homer2 AA/AA mice, suggesting a molecular basis for the deficit in cocaine aversion. These findings indicate that CaMKIIα-dependent phosphorylation of Homer2 gates the negative motivational valence of high-dose cocaine via regulation of mGlu5 binding, furthering an important role for dynamic changes in mGlu5-Homer interactions in addiction vulnerability. Competing Interests: The authors declare no competing financial interests. (Copyright © 2023 Szumlinski et al.)
Databáze:	MEDLINE
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