Mesocortical dopamine and HPA axis regulation: role of laterality and early environment.

The infralimbic (IL) cortex is importantly involved in regulating behavioral and physiological responses to stress, including those of the hypothalamic-pituitary-adrenal (HPA) axis. The mesocortical dopamine (DA) system is an important afferent modulator of this region, is highly stress sensitive and frequently shows functional hemispheric asymmetry. Postnatal handling stimulation facilitates development of cortical asymmetry and is also associated with optimal HPA axis regulation. The present study examines the poorly understood role of the mesocortical DA system in regulating HPA axis function in adult rats which were handled (H) or nonhandled (NH) postnatally. In the first experiment, unilateral intra-IL cortex injection of the DA (D1/D2) antagonist alpha-flupenthixol into either hemisphere significantly exaggerated the restraint stress-induced increases in plasma adrenocorticotrophic hormone and corticosterone in NH rats. In H rats, the same effect was lateralized to the right IL cortex. In a second experiment, post mortem neurochemical analysis of DAergic measures in the IL cortex was conducted in H and NH animals following either acute or repeated (5 times) restraint stress. DAergic measures in the right IL cortex were significantly correlated with reduced stress hormone activation in both H and NH rats, especially in repeatedly restrained rats. However, while H rats showed a significant rightward shift in DA metabolism with repeated stress experience, NH rats shifted DA metabolism to the left. It is suggested that, during stress, mesocortical DA release normally acts in an adaptive, negative feedback capacity preventing excessive HPA activation and, with repeated stress, the right IL cortex is particularly important in this capacity. As well, the selective enhancement of DA metabolism in the right IL cortex of H rats may underlie, in part, their typically superior ability to adapt to stress and constrain HPA activity.