Homer2 regulates alcohol and stress cross-sensitization

An interaction exists between stress and alcohol in the etiology and chronicity of alcohol use disorders, yet a knowledge gap exists regarding the neurobiological underpinnings of this interaction. In this regard, we employed an 11-day unpredictable, chronic, mild stress (UCMS) procedure to examine for stress-alcohol cross-sensitization of motor activity as well as alcohol consumption/preference and intoxication. We also employed immunoblotting to relate the expression of glutamate receptor-related proteins within subregions of the nucleus accumbens (NAC) to the manifestation of behavioral cross-sensitization. UCMS mice exhibited a greater locomotor response to an acute injection of 2g/kg alcohol than unstressed controls and this cross-sensitization extended to alcohol intake (0-20 percent), as well as to the intoxicating and sedative properties of 3 and 5g/kg alcohol, respectively. Regardless of prior alcohol injection (2g/kg), UCMS mice exhibited elevated NAC shell levels of mGlu1, GluN2b and Homer2, as well as lower phospholipase C within this subregion. GluN2b levels were also lower within the NAC core of UCMS mice. The expression of stress-alcohol locomotor cross-sensitization was associated with lower mGlu1 within the NAC core and lower extracellular signal-regulated kinase activity within both NAC subregions. As Homer2 regulates alcohol sensitization, we assayed also for locomotor cross-sensitization in Homer2 wild-type (WT) and knock-out (KO) mice. WT mice exhibited a very robust cross-sensitization that was absent in KO animals. These results indicate that a history of mild stress renders an animal more sensitive to the psychomotor and rewarding properties of alcohol, which may depend on neuroplasticity within NAC glutamate transmission.