Mild footshock stress results in the metabolic activation of the prefrontal cortical dopamine (DA) innervation, but does not augment DA utilization in mesolimbic areas (such as the nucleus accumbens septi, NAS) or the striatum. However, increases in either the intensity or duration of footshock stress increase DA utilization in the subcortical sites. DA afferents to the prefrontal cortex (PFC) hold corticofugal projection neurons under tonic inhibition. Previous data suggest that removal of these corticofugal glutamatergic neurons from tonic DA inhibition results in a transsynaptic alteration in the NAS, such that the DA innervation of the NAS is rendered hyperresponsive to certain perturbations. We therefore examined the effects of stress on subcortical DA systems in rats previously subjected to 6-hydroxydopamine lesions of the PFC DA innervation. Mild footshock stress resulted in an increase in concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the PFC, but not NAS or striatum, of sham-lesioned animals. Footshock resulted in a significant increase in the concentration of DOPAC in the nucleus accumbens of animals sustaining PFC lesions two weeks previously. The PFC lesion did not result in a stress-induced increase in DA release in the striatum. These results suggest that disruption of the PFC DA innervation results in an enhanced responsiveness of the mesolimbic DA innervation to stress. These data may help explain the stress-elicited exacerbation of the psychotic process in schizophrenia.