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Chronic cocaine use elicits changes in the pattern of gene expression within reinforcement‐related, dopaminergic regions. cDNA hybridization arrays were used to illuminate cocaine‐regulated genes in the nucleus accumbens (NAcc) of non‐human primates (Macaca fascicularis; cynomolgus macaque), treated daily with escalating doses of cocaine over one year. Changes seen in mRNA levels by hybridization array analysis were confirmed at the level of protein (via specific immunoblots). Significantly up‐regulated genes included: protein kinase A α catalytic subunit (PKA_cα); cell adhesion tyrosine kinase beta (PYK2); mitogen activated protein kinase kinase 1 (MEK1); and β‐catenin. While some of these changes exist in previously described cocaine‐responsive models, others are novel to any model of cocaine use. All of these adaptive responses coexist within a signaling scheme that could account for known …