The long suspected and recently demonstrated abnormality in neuroendocrine control in patients with severe depression indicates that the neurochemical and neuroanatomical analysis of the neuroendocrine response to stress may provide valuable information in understanding the etiology of severe endogenous depression. Rats were immobilized for 1, 2, 3 or 5 hours consecutively or 2 hours per day for 5 days, sacrificed and plasma corticosterone (as an index of the release of adrenocorticotropic hormone from the pituitary) and brain part noradrenaline, dopamine, and serotonin concentrations were determined fluorometrically. Plasma corticosterone and brain part monoamines were also measured in other rats given 2 hour immobilization stress one week after the intraventricular injection of the neurotoxins 6-hydroxydopamine and/or 5,6-dihydroxytryptamine. Plasma corticosterone increased by 30% to 50% after all periods of stress and serotonin was increased in all brain parts after 1, 2 or 3 hours of stress but not after 5 hours or chronic stress. Forebrain dopamine was decreased by 30% after 1 hour stress, slowly increased with increasing duration of stress becoming a marked increase of 85% over controls after prolonged or chronic stress. The destruction of catecholamine nerve terminals with 6-hydroxydopamine prevented the stress induced rise in brain part serotonin but had no effect on the plasma corticosterone response to immobilization stress. Destruction of serotonin nerve terminals with 5,6-dihydroxytryptamine potentiated by 50% the stress induced rise in plasma corticosterone. Plasma corticosterone after 2 hours immobilization stress was the same as controls in rats given both neurotoxins. These data support the hypothesis that ACTH release is stimulated by serotonergic neural activity.