Differential Roles of Accumbal GSK3β in Cocaine versus Morphine-Induced Place Preference, U50,488H-Induced Place Aversion, and Object Memory.

Previous research has demonstrated that activity of glycogen synthase kinase-3 (GSK3) is necessary for the rewarding effects of cocaine. In the present study, a conditional GSK3β gene knockdown model was used to determine if GSK3β activity specifically in the nucleus accumbens is important for cocaine conditioned reward. The roles of accumbal GSK3β in morphine conditioned reward, trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate salt (U50,488H)-induced conditioned place aversion, and cognitive function were also studied. Adult male and female GSK3β-floxed or wild-type mice were injected with adeno-associated virus/Cre into the nucleus accumbens to reduce expression of GSK3β and underwent behavioral testing 4 weeks later. The development of cocaine-induced conditioned place preference was significantly attenuated in mice with reduced levels of GSK3β in the nucleus accumbens, whereas the development of morphine-induced place preference remained intact. Conditional knockdown of GSK3β in the accumbens prevented the development of conditioned aversion produced by U50,488H, a κ-opioid receptor agonist. Cognitive memory tests revealed deficits in object location memory, but not novel object recognition in mice with accumbal GSK3β knockdown. These data demonstrate that GSK3β in the nucleus accumbens is required for cocaine conditioned place preference and U50,488H conditioned place aversion, as well as spatial memory in object location task, indicating differential roles of GSK3β in the psychostimulant and opiate reward process, as well as in memory for spatial locations and object identity. SIGNIFICANCE STATEMENT: Knockdown of GSK3β in the nucleus accumbens attenuated the development of cocaine-induced place preference, as well as conditioned place aversion to U50,488H, a κ-opioid receptor agonist. In contrast, the development of morphine place preference was not altered by GSK3β knockdown. GSK3β knockdown in nucleus accumbens impaired performance in the object location task, but not the novel object recognition task. These results elucidate different physiological roles of accumbal GSKβ in conditioned reward, aversion, and memory.