PT  - JOURNAL ARTICLE
AU  - Karen K. Szumlinski
AU  - Jacqueline Beltran
AU  - Eliyana van Doren
AU  - C. Leonardo Jimenez Chavez
AU  - Racquel D. Domingo-Gonzalez
AU  - Cindy M. Reyes
AU  - Alexis W. Ary
AU  - Andrew Lang
AU  - Weiruo Guo
AU  - Paul F. Worley
AU  - Kimberly M. Huber
TI  - Evidence for Phosphorylation-Dependent, Dynamic, Regulation of mGlu5 and Homer2 in Expression of Cocaine Aversion in Mice
AID  - 10.1523/ENEURO.0423-22.2023
DP  - 2023 Apr 01
TA  - eneuro
PG  - ENEURO.0423-22.2023
VI  - 10
IP  - 4
4099  - http://www.eneuro.org/content/10/4/ENEURO.0423-22.2023.short
4100  - http://www.eneuro.org/content/10/4/ENEURO.0423-22.2023.full
SO  - eNeuro2023 Apr 01; 10
AB  - 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 (Homer2AA/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 Homer2AA/AA mutation prevented activity-dependent phosphorylation of S216 Homer2 in cortical neurons, but Homer2AA/AA mice did not differ from wild-type (WT) controls with respect to Morris maze performance, acoustic startle, spontaneous or cocaine-induced locomotion. Homer2AA/AA mice exhibited signs of hypoanxiety similar to the phenotype of transgenic mice with a deficit in signal-regulated mGluR5 phosphorylation (Grm5AA/AA). However, opposite of Grm5AA/AA mice, Homer2AA/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 Homer2AA/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.