Serotoninergic control of food intake has been shown to be abnormal in obese persons with a decrease in serotoninergic tone. The neuroendocrine effects of intravenous I.V. administration of clomipramine (CMI), a serotonin uptake inhibitor, were studied in normal-weight (n=7) and obese subjects before (n=12) and after (n=6) dietary restriction. Under double-blind, placebo-controlled conditions, a single 12.5 mg dose of CMI was administered. There was no difference in baseline values of prolactin (PRL), corticotropin (ACTH) and cortisol in non-obese controls, obese before and obese after weight loss. CMI led to significant increases of PRL, ACTH, and cortisol concentrations in the controls as well as the obese group. The ACTH and cortisol responses to CMI in obese subjects were somewhat greater than the responses in normal-weight subjects. The area under the curve AUC for ACTH after clomipramine was 6202 +/- 976 pg/ml x 150 minutes for tile obese before weight loss and 3274 +/- 512 pg/ml x 150 minutes for the controls and the difference was significant at the level of p=0.052. The cortisol peak value after clomipramine was 163.71 +/- 14.31 ng/ml in the non-obese and 214.66 +/- 12.59 ng/ml in the obese (p=0.025). However, there was no difference in the obese subjects before and after weight loss. These data support the assumption that obese women have an abnormal sensitivity to the serotoninergic control of the hypothalamic pituitary adrenal axis (HPA), and that a mild weight loss does not significantly modify their serotoninergic tone.