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In response to neuronal activity, Homer2 is phosphorylated on S117\/S216 by calcium-calmodulin kinase II\u03b1 (CaMKII\u03b1), 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 (<jats:italic>Homer2<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>) were generated, and we determined their affective, cognitive and sensorimotor phenotypes, as well as cocaine-induced changes in conditioned reward and motor hyperactivity. The<jats:italic>Homer2<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>mutation prevented activity-dependent phosphorylation of S216 Homer2 in cortical neurons, but<jats:italic>Homer2<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>mice did not differ from wild-type (WT) controls with respect to Morris maze performance, acoustic startle, spontaneous or cocaine-induced locomotion.<jats:italic>Homer2<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>mice exhibited signs of hypoanxiety similar to the phenotype of transgenic mice with a deficit in signal-regulated mGluR5 phosphorylation (<jats:italic>Grm5<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>). However, opposite of<jats:italic>Grm5<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>mice,<jats:italic>Homer2<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>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<jats:italic>Homer2<jats:sup>AA\/AA<\/jats:sup><\/jats:italic>mice, suggesting a molecular basis for the deficit in cocaine aversion. These findings indicate that CaMKII\u03b1-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.<\/jats:p>","DOI":"10.1523\/eneuro.0423-22.2023","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T17:50:15Z","timestamp":1679939415000},"page":"ENEURO.0423-22.2023","source":"Crossref","is-referenced-by-count":1,"title":["Evidence for Phosphorylation-Dependent, Dynamic, Regulation of mGlu5 and Homer2 in Expression of Cocaine Aversion in Mice"],"prefix":"10.1523","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1078-1077","authenticated-orcid":false,"given":"Karen K.","family":"Szumlinski","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Beltran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliyana","family":"van Doren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. 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