The dopamine D2 receptor (DRD2) and dopamine transporter (DAT) play a regulatory role in dopaminergic neurotransmission and thus play an important role in drug addiction. The prefrontal cortex (PFC), a critical part of the mesencephalic dopaminergic system, is thought to be involved in the development and maintenance of drug addiction. The addiction to ketamine is thought to induce behavioral effects primarily through actions on the central nervous system. However, the neural mechanism underlying the effects of ketamine addiction remains unclear. In this study, we investigate the involvement of PFC DRD2 and DAT in ketamine addiction effects after ketamine administration for 10 weeks in nonhuman primates. To this end, after administering ketamine to rhesus monkeys for 10 weeks, we assessed changes in body weight and behavior. Additionally, neuronal changes in the PFC were examined by hematoxylin and eosin (HE) staining; the DRD2 and DAT mRNA and protein expression levels in the PFC were determined by real-time PCR and Western blot analysis, respectively. After 10-week ketamine administration, the assessment of the manifestations of toxicity in rhesus monkeys revealed significant changes in body weight and behavior, decreased DRD2 and DAT mRNA and protein expression in the PFC, and histological abnormalities including neuronal eosinophilia, pyknosis and disorderly arrangement of neurons in the PFC. These results suggest that the reduced expression of DRD2 and DAT in PFC could be involved in the behavioral and the neurological changes induced by ketamine administration, which may play an important role in the molecular mechanisms of ketamine addiction.