Nonphosphorylatable Src Ser75 Mutation Increases Ethanol Preference and Consumption in Mice

Src is highly expressed in CNS neurons and contributes not only to developmental proliferation and differentiation but also to high-order brain functions, such as those contributing to alcohol consumption. Src knock-out mice exhibit no CNS abnormalities, presumably due to compensation by other Src family kinases (SFKs), but have a shortened lifespan and osteopetrosis-associated defects, impeding investigations of the role of Src on behavior in adult mice. However, the Unique domain of Src differs from those in other SFKs and is phosphorylated by cyclin-dependent kinase 1 (Cdk1) and Cdk5 at Ser75, which influences its postmitotic function in neurons. Therefore, ethanol consumption in mice harboring nonphosphorylatable (Ser75Ala) or phosphomimetic (Ser75Asp) Src mutants was investigated. Mice harboring the Ser75Ala Src mutant, but not the Ser75Asp mutant, had a higher preference for and consumption of solutions containing 5% and 10% ethanol than wild-type mice. However, plasma ethanol concentrations and sensitivities to the sedative effects of ethanol were not different among the groups. In mice harboring the Ser75Ala Src mutant, the activity of Rho-associated kinase (ROCK) in the striatum was significantly lower and Akt Ser473 phosphorylation was significantly higher than in wild-type mice. These results suggest that Src regulates voluntary ethanol drinking in a manner that depends on Ser75 phosphorylation.