Chronic single neuronal recording techniques were applied to investigate the involvement of the medial prefrontal cortex (mPFC) during cocaine self-administration in the rat. Rats were trained to press a lever for cocaine under continuous reinforcement and fixed ratio schedules. Different patterns of phasic neuronal activity changes were found to be associated with lever-pressing for cocaine. The neuronal responses could be classified into five categories: 1) increases in neuronal firing before the lever press (15 out of 121 neurons, 12.4%); 2) decreases in neuronal firing before the lever press (13 neurons, 10.7%); 3) increases in neuronal firing after cocaine infusion (4 neurons, 3.3%); 4) decreases in neuronal firing after cocaine infusion (32 neurons, 26.4%); and 5) no alteration of neuronal activity throughout the self-administration session (67 neurons, 55.4%). The anticipatory responses, i.e., neuronal activity appearing before the lever press, were observed for both the continuous reinforcement and fixed ratio schedules. In a few cases, alteration of firing rate was not observed for the first lever press but appeared before subsequent lever presses in fixed ratio schedules. Eliminating cocaine abolished the inhibitory neuronal responses observed after lever press, suggesting that these inhibitory responses after cocaine self-administration were attributable to the pharmacologic effect of cocaine. The data provide initial electrophysiological evidence that the mPFC may play a role in mediating the task sequencing which leads to cocaine self-administration.