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

• Published in: eNeuro Vol. 10; no. 4; p. ENEURO.0423-22.2023
• Main Authors: Szumlinski, Karen K, Beltran, Jacqueline, van Doren, Eliyana, Jimenez Chavez, C Leonardo, Domingo-Gonzalez, Racquel D, Reyes, Cindy M, Ary, Alexis W, Lang, Andrew, Guo, Weiruo, Worley, Paul F, Huber, Kimberly M
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 01.04.2023
• Subjects: Animals; Cocaine - pharmacology; Conditioning, Psychological; Mice; Mice, Knockout; Mice, Transgenic; New Research; Phosphorylation; anxiety; mGlu5; Homer proteins; cocaine; emotionality
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/ENEURO.0423-22.2023

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 ( ) were generated, and we determined their affective, cognitive and sensorimotor phenotypes, as well as cocaine-induced changes in conditioned reward and motor hyperactivity. The mutation prevented activity-dependent phosphorylation of S216 Homer2 in cortical neurons, but mice did not differ from wild-type (WT) controls with respect to Morris maze performance, acoustic startle, spontaneous or cocaine-induced locomotion. mice exhibited signs of hypoanxiety similar to the phenotype of transgenic mice with a deficit in signal-regulated mGluR5 phosphorylation ( ). However, opposite of mice, 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 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.