Cocaine‐ and amphetamine‐regulated transcript peptide in the nucleus accumbens shell inhibits cocaine‐induced locomotor sensitization to transient over‐expression of α‐Ca 2+ 2+ /calmodulin‐dependent protein kinase II II

摘要

Abstract Cocaine and amphetamineregulated transcript (CART ) peptide is a widely distributed neurotransmitter that attenuates cocaineinduced locomotor activity when injected into the nucleus accumbens (NA c). Our previous work first confirmed that the inhibitory mechanism of theCART peptide on cocaineinduced locomotor activity is related to a reduction in cocaineenhanced phosphorylated Ca2+ /calmodulindependent protein kinaseII ?(pCaMKII ? and the enhancement of cocaineinduced D3R function. This study investigated whetherCART peptide inhibited cocaineinduced locomotor activity via inhibition of interactions betweenpCaMKII ?and the D3 dopamine receptor (D3R). We demonstrated that lentivirusmediated gene transfer transiently increasedpCaMKII ?expression, which peaked at 10燿ays after microinjection into the ratNA c shell, and induced a significant increase in Ca2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15爉g/kg). However, western blot analysis and coimmunoprecipitation demonstrated thatCART peptide treatment in lentivirustransfected CaMKII ?overexpressingNA c rat tissues or cells prior to cocaine administration inhibited the cocaineinduced Ca2+ influx and attenuated the cocaineincreasedpCaMKII ?expression in lentivirustransfected CaMKII ?overexpressing cells.CART peptide decreased the cocaineenhanced phosphorylatedcAMP response element binding protein (pCREB ) expression via inhibition of thepCaMKII ?D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirustransfected CaMKII ?overexpressing cells. These results provide strong evidence for the inhibitory modulation ofCART peptide in cocaineinduced locomotor sensitization.Cover Image for this issue: doi:10.1111/jnc.14187 .