Chronic multi-channel single unit recordings of neuronal responses in prefrontal cortex (PFC) and nucleus accumbens (NAc) were made in 9 male Sprague Dawley rats to determine patterns of neuronal activity during heroin self-administration. Up to 32 neurons were recorded simultaneously in these two brain regions while rats lever pressed on a continuous reinforcement schedule for intravenous infusion of heroin (30 microg/kg/infusion). The variety of neuronal responses observed before and after each self-administered heroin infusion can be classified according to the following categories: (1) neurons that increased or (2) decreased their activity immediately before the lever press; (3) neurons that increased or (4) decreased their activity after the heroin infusion; and, (5) neurons that did not alter their activity either before or after the lever press for heroin infusion. The majority (69% in the PFC and 65% in the NAc) of neurons sampled fell into this last category of no change, indicating that a selected fraction becomes active during this specific task. In general, NAc neurons displayed more post-heroin responses than PFC neurons while the proportion of neurons showing responses before the lever press was similar in the mPFC and the NAc. This initial description of the responses of PFC and NAc neurons during heroin self-administration suggests that the neuronal circuit of the mesocorticolimbic system is involved in heroin self-administration. This circuit appears to contribute both to the initiation of drug-seeking behavior (pre-lever press phasic neuronal responses), as well as the action of heroin infusion itself (post-infusion phasic neuronal responses) by activation of different subsets of neurons.