- Addictive drugs, such as cocaine, cause long-lasting neural changes in prefrontal cortex. It has been hypothesized that these changes affect the behavioural control mediated by orbitofrontal cortex. To test this hypothesis, rats were given injections of cocaine (30 mg/kg/d, i.p.) or vehicle for 14 days and then trained after a 2-week withdrawal period in an odor discrimination task sensitive to the effects of orbitofrontal cortex lesions. We found that cocaine-treated rats, who demonstrated long-lasting sensitization to the locomotor activating effects of cocaine, failed to show normal changes in response latency during discrimination learning and were also slower than controls to acquire serial reversals. These behavioural impairments are identical to the effects of orbitofrontal cortex lesions in this task and show that cocaine exposure in rats can cause long-lasting effects on orbitofrontal-dependent functions. Notably, these effects were not correlated with increases in locomotor activity linked to cocaine-induced psychomotor sensitization observed before or after training, suggesting that the brain changes underlying the behavioural effects in the discrimination task are different from those mediating psychomotor sensitization.