The hypothesis was tested that the neural lobe of the pituitary may modulate the release of anterior pituitary hormones. The neural lobe of anesthetized lactating rats was electrically stimulated at 30 Hz (5 sec on and 5 sec off) for 3 min while taking blood samples for RIA of ACTH. Plasma ACTH increased within 3 min by 22 +/- 9% (average +/- SEM; P less than 0.025) in intact rats and by 38 +/- 17% (P less than 0.025) in rats where the nerve supply to the median eminence and neural lobe was interrupted. Electrical stimulation of the anterior pituitary was ineffective. No significant changes in plasma ACTH were observed in rats with coagulated hypophysial portal vessels or in Brattleboro rats with congenital diabetes insipidus. Apparently, neither peripheral plasma vasopressin (estimated at 150 microU/ml maximum) nor intermediate lobe ACTH could account for the observed rise in ACTH. Results suggest a vasopressin dependent modulation of ACTH release by the neural lobe, mediated either by axon collaterals to the median eminence or by a vascular interconnection between posterior and anterior pituitaries.