Evidence for phosphorylation-dependent, dynamic, regulation of mGlu5 and Homer2 in expression of cocaine aversion in mice.

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 controls with respect to Morris maze performance, acoustic startle, spontaneous or cocaine-induced locomotion. Homer2 AA/AA mice exhibited signs of hypo-anxiety 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- 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. Significance statement Globally, psychostimulant use has again risen to reach epidemic proportions, particularly in the United States. Yet, we continue to face a knowledge gap regarding the biological bases of psychostimulant addiction vulnerability to inform disease prognosis and treatment-based recovery. Herein, we show that the psychomotor stimulant cocaine induces the uncoupling of the mGlu5 glutamate receptor from its scaffolding protein Homer2 in brain. Using a transgenic mouse model with deficits cocaine-induced uncoupling of mGlu5-Homer2, we demonstrate an important role for Homer2 scaffolding of mGlu5 in regulating cocaine's aversive properties, without influencing cocaine reward. Findings suggest that environmental factors, to include cocaine exposure, that affect mGlu5-Homer2 scaffolding dynamics may contribute to an individual's subjective response to cocaine to influence addiction vulnerability.