The medial prefrontal cortex determines the accumbens dopamine response to stress through the opposing influences of norepinephrine and dopamine.

Although the medial prefrontal cortex (mpFC) appears to constrain stress responses, indirect evidences suggest that it might determine the stress response of the mesoaccumbens dopamine (DA) system. To test this hypothesis, we first evaluated the dynamics of norepinephrine (NE) and DA release in the mpFC and of DA release in the nucleus accumbens (NAc) of acutely stressed rats. Then, we tested the effects of selective depletion of NE or DA in the mpFC (by local 6-hydroxydopamine infusion following desipramine or 1-[2[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine(GBR 12909) on stress-induced changes in mesoaccumbens DA release. Rats experiencing restraint stress for 240 min showed an initial, short-lived increase of NE outflow in the mpFC and of DA in the NAc. These responses were followed by a sustained increase of DA in the mpFC and by a decrease to below resting levels of DA in the NAc. Moreover, selective prefrontal NE depletion eliminated the increase of NE in the mpFC and of DA in the NAc, and selective depletion of mesocortical DA eliminated the enhancement of mpFC DA as well as the inhibition of mesoaccumbens DA, without affecting basal catecholamines outflow. These results demonstrate that the opposing influences of mpFC NE and DA determine mesoaccumbens DA response to stress and suggest that alterations of this mechanism may be responsible for some major psychopathological outcomes of stress.