The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration

•CART peptide inhibited cocaine-mediated locomotion after single cocaine injection.•The inhibitory effect of CART peptide was lost after chronic cocaine administration.•The effect of CART peptide was not recovered even after cocaine withdrawal.•The persistent loss of CART peptide effect suggests its role in cocaine addiction. CART peptide is known for having an inhibitory effect on cocaine- and dopamine-mediated actions after acute administration of cocaine and dopamine. In this regard, it is postulated to be a homeostatic, regulatory factor on dopaminergic activity in the nucleus accumbens (NAc). However, there is no data on the effect of CART peptide after chronic administration of cocaine, and this study addresses this. It was found that CART peptide blunted cocaine-induced locomotion (LMA) after acute administration of cocaine, as expected, but it did not affect cocaine-mediated LMA after chronic administration of cocaine. The loss of CART peptide's inhibitory effect did not return for up to 9 weeks after stopping the repeated cocaine administration. It may not be surprising that homeostatic regulatory mechanisms in the NAc are lost after repeated cocaine administration, and that this may be a mechanism in the development of addiction.