The status of serotonin as a putative neurotransmitter involved in the control of the secretion of corticotrophin-releasing activity from the rat hypothalamus has been further investigated. The experimental model used for the investigation was the rat hypothalamus incubated in vitro. It was confirmed that serotonin causes a dose-related release of corticotrophin-releasing activity from the tissue and it was shown that this effect was mimicked by the addition to the tissue of chlorimipramine or d-fenfluramine, two drugs expected to cause an increase in the concentration of serotonin in the synaptic cleft. The effect of the latter drug was greatly reduced by the simultaneous addition of either methysergide or metergoline.Destruction of serotonin-containing nerve terminals in the hypothalamus was caused by the intraventricular administration of the neurotoxic drug 5,7-dihydroxytryptamine. This treatment resulted in an 84% reduction of the serotonin concentration in the hypothalamus 12 days later. Hypothalami taken from animals 12 days after treatment with the drug secreted corticotrophin-releasing activity in basal amounts equal to those found in tissues taken from control rats, but showed supersensitivity in response to added serotonin. No such supersensitivity was seen in response to d-fenfluramine and a diminished response to chlorimipramine was noted. Despite its intraventricular route of administration, 5,7-dihydroxytryptamine was found to increase the sensitivity of segments of anterior pituitary gland in vitro to low doses of preparations containing corticotrophin releasing factor.These results are consistent with the view that endogenous serotonin can act as a stimulator of the secretion of corticotrophin-releasing activity from the rat hypothalamus. They also suggest that conclusions about the control of the release of this trophic material inferred from measurements of corticotrophin or corticosterone in the circulation must be viewed with caution when the drug 5,7-dihydroxytryptamine has been used, because of the development of supersensitivity both in the hypothalamus and in the anterior pituitary gland.

It has previously been reported that sodium valproate (Epilim) lowers plasma ACTH levels in Nelson's syndrome. This report describes further experience with its use. Ten patients with Nelson's syndrome were treated with sodium valproate (600-1200 mg/day) for 5-32 weeks. Plasma ACTH was measured by cytochemical methods and RIA. Initial treatment for 5-12 weeks significantly (P less than 0.005) lowered plasma ACTH from a pretreatment mean of 2460 +/- 1870 ng/liter to 480 +/- 330 ng/liter, and the ACTH circadian rhythm was restored in two patients. On discontinuing treatment, plasma ACTH levels remained suppressed for 3 weeks and rose to pretreatment values in 5-12 weeks. Two patients' plasma ACTH levels failed to show a second response to treatment, while a third patient had a favorable second response to treatment over 32 weeks. In six patients, skin pigmentation lightened with treatment, and in one patient, a reduction in size of a pituitary microadenoma, demonstrated radiographically, occurred with treatment. gamma-Aminobutyric acid and sodium valproate were shown to be ineffective in inhibiting ACTH secretion from cultured pituitary tumor cells from a patient with Nelson's syndrome. The results show that sodium valproate is effective in some cases of Nelson's syndrome. We suggest that it reduces the hypersecretion of ACTH by enhancing gamma-aminobutyric acid function in the hypothalamus, thereby inhibiting the release of corticotropin-releasing factor.