Chronic hypercortisolemia attenuates yohimbine (YOH)-induced increments in plasma levels of the sympathetic neurotransmitter norepinephrine (NE). The present study used in vivo microdialysis to study the effects of hypercortisolemia on YOH-induced release of NE in the brain. Cortisol (25 mg/kg.day) or saline was infused sc into rats for 7 days via an osmotic minipump. Microdialysate and plasma concentrations of NE and its metabolites dihydroxyphenylglycol and methoxyhydroxyphenylglycol were measured before and after YOH (1 mg/kg, iv) administration in conscious animals, with microdialysate and plasma collections beginning 20-24 h after probe implantation. Chronic cortisol treatment resulted in attenuated NE, dihydroxyphenylglycol, and methoxyhydroxyphenylglycol responses in both microdialysate and plasma. The results indicate that YOH increases central neural as well as peripheral release, reuptake, turnover, and metabolism of NE and that hypercortisolemia suppresses these responses.