The effects of left, right or bilateral depletion of the mesocortical dopamine innervation (medial prefrontal and anterior cingulate) with 6-hydroxydopamine were examined in male Sprague-Dawley rats tested for susceptibility to cold restraint-induced gastric stress pathology. All three types of lesions tended to potentiate the development of stress pathology (i.e. ulceration) in comparison to restrained shams, but only right cortical dopamine depletion produced a highly significant increase. The results support a protective role for mesocortical dopamine in helping the organism cope with stressful situations, and extend previous findings suggesting that dopamine activation in the right cortex is preferentially associated with uncontrollable stress. The right cortex is hypothesized to be at the top of a hierarchy in the processing of such stressful inputs, and endogenous dopaminergic modulation facilitates adaptive responses. Subcortical dopamine terminal regions were also examined for dopamine content and turnover. In addition to depleting cortical dopamine, the three lesion groups showed highly specific alterations in the status of subcortical dopamine systems, compared to either restrained or non-restrained shams. Left brain lesions resulted in significant bilateral increases in amygdala dopamine turnover. Right cortical lesions induced significant bilateral reductions of striatal dopamine content. Bilateral lesions increased dopamine content in the left amygdala and decreased dopamine in the right nucleus accumbens. Also in this group, dopamine turnover was increased in the right nucleus accumbens and decreased in the right amygdala. The data suggest that increases in stress vulnerability induced by cortical lesions may be related, in part, to neurochemical alterations in subcortical structures previously shown to modulate gastric stress pathology. The results also indicate that brain organization is inherently asymmetrical with respect to the regulation of responses to stress, which may be of significance for human psychopathology and its exacerbation by stress.