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Several studies in humans and rodents suggest an association between impulsivity and activity of the stress response on the one hand and addiction vulnerability on the other. The neural cell adhesion molecule (NCAM) has been related to several neuropsychiatric disorders in humans. Constitutively NCAM‐deficient (−/−) mice display enhanced novelty‐induced behavior and hyperfunction of the hypothalamic‐pituitary‐adrenal axis. Here we hypothesize that NCAM deficiency causes an altered response to cocaine. Cocaine‐induced behaviors of NCAM−/− mice and wild‐type (+/+) littermates were analyzed in the conditioned place preference (CPP) test. c‐fos mRNA levels were investigated by quantitative polymerase chain reaction (qPCR) to measure neural activation after exposure to the cocaine‐associated context. NCAM−/− mice showed an elevated cocaine‐induced sensitization, enhanced CPP, impaired extinction, and potentiated cocaine‐induced hyperlocomotion and CPP after extinction. NCAM−/− showed no potentiated CPP as compared with NCAM+/+ littermates when a natural rewarding stimulus (ie, an unfamiliar female) was used, suggesting that the behavioral alterations of NCAM−/− mice observed in the CPP test are specific to the effects of cocaine. Activation of the prefrontal cortex and nucleus accumbens induced by the cocaine‐associated context was enhanced in NCAM−/− compared with NCAM+/+ mice. Finally, cocaine‐induced behavior correlated positively with novelty‐induced behavior and plasma corticosterone levels in NCAM−/− mice and negatively with NCAM mRNA levels in the hippocampus and nucleus accumbens in wild‐type mice. Our findings indicate that NCAM deficiency affects cocaine‐induced CPP in mice and support the view that hyperfunction of the stress response system and reactivity to novelty predict the behavioral responses to cocaine.

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