Glycogen Synthase Kinase 3β Is a Key Regulator in the Inhibitory Effects of Accumbal Cocaine- and Amphetamine-Regulated Transcript Peptide 55–102 on Amphetamine-Induced Locomotor Activity

Microinjection of cocaine- and amphetamine-regulated transcript (CART) peptide 55–102 into the nucleus accumbens (NAcc) core significantly attenuates psychostimulant-induced locomotor activity. However, the molecular mechanism remains poorly understood. We examined the phosphorylation levels of Akt, glycogen synthase kinase 3β (GSK3β), and glutamate receptor 1 (GluA1) in NAcc core tissues obtained 60 min after microinjection of CART peptide 55–102 into this site, followed by systemic injection of amphetamine (AMPH). Phosphorylation levels of Akt at Thr308 and GSK3β at Ser9 were decreased, while those of GluA1 at Ser845 were increased, by AMPH treatment. These effects returned to basal levels following treatment with CART peptide 55–102. Furthermore, the negative regulatory effects of the CART peptide on AMPH-induced changes in phosphorylation levels and locomotor activity were all abolished by pretreatment with the S9 peptide, an artificially synthesized indirect GSK3β activator. These results suggest that the CART peptide 55–102 in the NAcc core plays a negative regulatory role in AMPH-induced locomotor activity by normalizing the changes in phosphorylation levels of Akt-GSK3β, and subsequently GluA1 modified by AMPH at this site. The present findings are the first to reveal GSK3β as a key regulator of the inhibitory role of the CART peptide in psychomotor stimulant-induced locomotor activity.