Glucocorticoid Receptors in the Prefrontal Cortex Regulate Stress-Evoked Dopamine Release and Aspects of Executive Function

Enhanced dopamine release in the prefrontal cortex (PFC) is a well-documented response to acute stress. However, the underlying mechanism(s) for this response is unknown. We hypothesized that stress-evoked dopamine release in the PFC would be reduced by blockade of glucocorticoid receptors. Methods. In vivo microdialysis was performed in freely-moving rats subjected to an acute tail-pinch stress. A glucocorticoid receptor antagonist, RU-38486, was reverse-dialyzed into the ventral tegmental area or medial PFC while dopamine was continuously sampled from the medial PFC. Dopamine in microdialysates was separated by high-pressure liquid chromatography and quantified by electrochemical detection. The functional impact of stress-evoked dopamine release was demonstrated, using a cognitive task dependent on the PFC, and sensitive to impairment in working memory. Results. Blocking glucocorticoid receptors in the medial PFC with RU-38486 significantly attenuated stress-evoked dopamine release in the same brain region. However, blocking glucocorticoid receptors in the ventral tegmental area did not attenuate stress-evoked dopamine release in the medial PFC. Furthermore, blocking glucocorticoid receptors in this area of cortex attenuated stress-induced impairments in working memory. Taken together, our data suggest that glucocorticoids act locally within the PFC to modulate mesocortical dopamine release leading to the cognitive impairments observed during acute stress.