The normal diurnal variation in plasma corticosterone (COR) was abolished and the response to ether stress was enhanced at 3 days following the production of medial forebrain bundle (MFB) lesions in male rats. However, by 7 days following surgery, basal plasma COR levels and the response to ether stress appeared normal. These alterations and subsequent recovery of pituitary-adrenal activity were accompanied by decreasing hypothalamic synaptosomal uptake of serotonin (5HT) and increasing synaptosomal uptake of dopamine (DA), evident at 3 and continuing at 7 days following the lesion. Uptake of norepinephrine (NE) was not affected at 3 days but showed a reduction at 7 days following surgery. The results suggest that disruption of ascending 5HT and NE fibers to the hypothalamus can alter pituitary-adrenal activity but that normal activity recovers by 7 days following the lesion. The correlation between recovery of pituitary-adrenal activity and increases in the normal uptake of hypothalamic DA suggest that DA may interact with 5HT and NE systems in the normal control of adrenocorticotrophin (ACTH) release.