Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopathology through regulation of subcortical, especially mesoaccumbens, DA functioning. In these experiments we demonstrate that the high vulnerability to stress-induced 'despair' and mesoaccumbens DA inhibition, exhibited by mice of the inbred strain C57BL/6 (C57) in a common animal model of depression, depends on their being highly susceptible to stress-induced mesocortical DA activation. Thus, C57 mice but not mice of the DBA/2 strain showed an extremely high level of immobility on their first experience with the forced swimming test (FST) as well as immediate and strong activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA metabolism and release. In addition, the behavioral and the mesoaccumbens DA responses to FST in C57 mice were reduced and reversed, respectively, by bilateral mesocortical DA depletion. Finally, chronic treatment with the antidepressant clomipramine reduced immobility and eliminated both mesocortical DA activation and mesoaccumbens DA inhibition in response to FST. These results suggest that a genetically determined susceptibility to stress by the mesocortical DA system may favor the development of pathological behavioral responses through inhibition of subcortical DA transmission.