Glucocorticoid modulation of the mesocortical dopamine system and aspects of executive function

Enhanced dopamine efflux in the medial prefrontal cortex is a well-documented response to acute stress and is associated with deficits in cognitive performance. However, the underlying mechanism(s) for this response is unknown. The mesocortical dopamine system is comprised of dopamine neurons in the ventral tegmental area that receive excitatory input from and send reciprocal projections to the medial prefrontal cortex. We hypothesize that glucocorticoid receptors in the medial prefrontal cortex modulate the activity of this descending glutamatergic input to the ventral tegmental area during stress. Using in vivo microdialysis, we demonstrate that blocking glucocorticoid receptors locally within the rat medial prefrontal cortex, but not in the ventral tegmental area, attenuates mesocortical dopamine efflux to acute tail-pinch stress. Acute stress leads to a significant increase in glutamate release in the ventral tegmental area that is prevented by blockade of glucocorticoid receptors in the medial prefrontal cortex. The functional impact of enhanced mesocortical dopamine efflux evoked by acute stress was demonstrated using cognitive tasks measuring executive function. Exposure to acute tail-pinch stress selectively impaired performance on a working memory and set-shifting task. Conversely, performance on a non-delayed random foraging or reversal learning task that do not require the medial prefrontal cortex were unaffected by stress. Notably, stress-induced impairments in working memory were attenuated by blockade of glucocorticoid receptors in the medial prefrontal cortex. Taken together, these data suggest that glucocorticoids act locally within the medial prefrontal cortex to modulate mesocortical dopamine efflux by potentiation of glutamatergic drive onto dopamine neurons in the ventral tegmental area leading to the executive function impairments observed during acute stress.Medicine, Faculty ofGraduat