PT  - JOURNAL ARTICLE
AU  - Xiangdang Shi
AU  - Jeffrey L. Barr
AU  - Eva von Weltin
AU  - Cassandra Wolsh
AU  - Ellen M. Unterwald
TI  - Role of accumbal GSK3β in drug reward, aversion, and place memory
AID  - 10.1124/jpet.119.259283
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.259283
4099  - http://jpet.aspetjournals.org/content/early/2019/08/16/jpet.119.259283.short
4100  - http://jpet.aspetjournals.org/content/early/2019/08/16/jpet.119.259283.full
AB  - 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, U50,488H-induced conditioned place aversion, and cognitive function were also studied. Adult male and female GSK3β-floxed or wild-type mice received AAV-Cre infusions into the nucleus accumbens to reduce expression of GSK3β and underwent behavioral testing three 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 the kappa opioid receptor agonist U50,488H. Cognitive memory tests revealed that object location, but not novel object recognition, was impaired in the mice with accumbal GSK3β knockdown. These data demonstrate that GSK3β in the nucleus accumbens is required for both cocaine conditioned reward and U50,488H conditioned aversion, as well as spatial memory in object location task, indicating differential roles of GSK3β in psychostimulant and opiate reward process, as well as in memory for object identity and spatial locations.SIGNIFICANCE STATEMENT Knockdown of GSK3β in the nucleus accumbens attenuated the development of cocaine-induced place preference, as well as conditioned place aversion to the kappa opioid receptor agonist, U50,488. In contrast, the development of morphine-induced place preference was not altered by GSK3β knockdown. GSK3β knockdown in nucleus accumbens impaired performance in the novel location task, but not the novel object recognition task. These data provide insight into the different physiological roles of accumbal GSKβ in conditioned reward, aversion and memory.