Voltammetry was used to study the role of prefrontal cortex (PFC) dopamine (DA) in modulating the nucleus accumbens (NAcc) DA response to stress. Signal increases elicited in NAcc by 15 min of restraint were monitored in freely-behaving rats following intra-PFC microinjections of D1 and D2 receptor-selective drugs. The exact site of injection was first determined by assessing the electrochemical response to stress at two dorsal-ventral levels of PFC. Consistent with previous reports, a pronounced stress response was observed ventrally at sites within the infralimbic PFC but not dorsally within the superficial layers of PFC. When microinjected into the infralimbic PFC, the D1 receptor antagonist SCH 23390 significantly enhanced the NAcc stress response. While the D1 receptor agonist SKF 38393 tended to decrease the NAcc stress response, it failed to do so reliably. Neither sulpiride (D2 receptor antagonist) nor quinpirole (D2 receptor agonist) had a significant effect. Finally, systemic administration of the selective DA uptake inhibitor GBR 12909 dose-dependently potentiated stress-induced signal increases in NAcc and in PFC, indicating that the electrochemical responses to stress in both regions were due primarily to increases in extracellular DA levels. Together, these data add to other evidence indicating that the PFC exerts an inhibitory influence on subcortical DA transmission. Specifically, the present results suggest that the NAcc DA response to stress is dampened by the concurrent activation of meso-PFC DA neurons and that this action is mediated, at least in part, by D1 receptors in PFC.