Cocaine‐ and amphetamine‐regulated transcript peptide in the nucleus accumbens shell inhibits cocaine‐induced locomotor sensitization to transient over‐expression of α‐Ca2+/calmodulin‐dependent protein kinase II
Cocaine‐ and amphetamine‐regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine‐induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine‐induced locomotor activity is related to a reduction in cocaine‐enhanced phosphorylated Ca2+/calmodulin‐dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine‐induced D3R function. This study investigated whether CART peptide inhibited cocaine‐induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus‐mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc 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 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus‐transfected CaMKIIα‐over‐expressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine‐induced Ca2+ influx and attenuated the cocaine‐increased pCaMKIIα expression in lentivirus‐transfected CaMKIIα‐over‐expressing cells. CART peptide decreased the cocaine‐enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα‐D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus‐transfected CaMKIIα‐over‐expressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine‐induced locomotor sensitization.
Cover Image for this issue: doi: 10.1111/jnc.14187.
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