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The gas hydrogen sulphide (H2S) is normally produced in large amounts in the central nervous system during the metabolism of sulphur-containing aminoacids. H2S was recently shown to influence long-term potentiation in the rat hippocampus; this finding suggested that the gas may act as a neuromodulator in the brain. We therefore tested the effect of the gas on the release of corticotropin-releasing hormone (CRH) from rat hypothalamic explants. CRH immunoreactivity in the incubation media was taken as a marker of peptide release. We found that the addition of NaHS to incubation media was consistently associated with a concentration-dependent decrease in KCl-stimulated CRH release, whereas basal secretion was unaffected. Increased endogenous H2S production may be also obtained using an indirect precursor of H2S formation, S-adenosyl-L-methionine (SAMe). The latter mimicked the effects of NaHS, since it reduced potassium-stimulated CRH release. In vivo, SAMe showed no effect on hypothalamo-pituitary-adrenal (HPA) function under resting conditions, but inhibited stress-related glucocorticoid increase.

The anticancer drug hydroxyurea (HU) at doses of 300-800 mg/kg/day causes a dramatic lethality (up to 100% after a 5-day treatment) in hypophysectomized as well as in adrenalectomized rats drinking physiological saline + 5% glucose. Mortality in controls was less than 10% over a 5-day period. Adrenal stimulatory or replacement therapies protect pituitary- or adrenal-ablated rats against HU toxicity. They also counteract white blood cell changes induced by the drug. HU (30-800 mg/kg) induces a dose-dependent increase of plasma corticosterone in normal rats after single or repeated treatments that is not observed in hypophysectomized animals. HU also increases plasma levels of epinephrine, although this finding cannot account for the rise in plasma corticosterone; indeed, it is secondary to a strong rise in plasma corticosterone. The stimulation of the hypothalamic-hypophyseal-adrenal axis induced by HU is responsible for the drug-induced adrenocortical activation. This activation appears to be a valuable defence mechanism protecting intact rats against HU lethality, and its failure causes the dramatic HU lethality in pituitary- or adrenal-ablated animals.

A single i.p. injection of vincristine (1000 microgram/kg) into rats increased the plasma concentration of corticosterone after a latent period of 4 hr; the effect lasted for 48 hr. The response was dose related with the threshold dose being 100 microgram/kg and the maximal effect occurring after 250 microgram/kg. Vincristine also increased plasma corticosterone levels in hypophysectomized rats, suggesting that the drug may have a direct action on the adrenal gland. The injection of 500 or 1000 microgram/kg also reduced the plasma concentration of thyroid-stimulating hormone. Twelve and 18 hr after the injection of vincristine (1000 microgram/kg), the plasma concentration of thyroid-stimulating hormone was reduced, whereas the hypothalamic content of norepinephrine, a neurotransmitter involved in the regulation of thyrotropin-releasing hormone-thyroid-stimulating hormone secretion, remained unchanged. The adrenocortical stimulation produced by vincristine may play some role in the antineoplastic effects of this drug.

Daily i.p. injection of reserpine for 9 days strongly depletes hypothalamic norephinephrine (NE); after an initial activation, adrenocortical function returns to control values by the 5th day. Tyrosine hydroxylase (TH) activity in the brain stem of reserpine-treated rats exhibits a progressive increase. Alpha-methyl-para-tyrosine (chi-MpT) in rats chronically pretreated with reserpine provokes adrenocortical activation and a further decrease of hypothalamic NE. Exogenous ACTH in the same animals revealed an unimpaired adrenocortical reactivity after prolonged treatment with reserpine. These results seem to suggest that the disappearance of adrenocortical activation following long-term treatment with reserpine is due to the stimulated formation of a small functional pool of NE available for the tonic inhibition of CRF-ACTH secretion.

An H2-antagonist, cimetidine, reduces in the rat normal plasma corticosterone levels and strongly antagonizes their increase after cold stress. This latter effect is dose dependent. Plasma corticosterone reduction by cimetidine lasts 4 h both in normal and stress situations. Both a hypophyseal or adrenal site of action of the drug may be involved in the inhibition of adrenocortical secretion.

1. The effect of a pharmacologically induced increase or depletion of brain monoamines (5-hydroxytryptamine, noradrenaline, dopamine) was investigated with respect to adrenocortical function.2. No strict correlation was found between the depletion of brain amine stores induced by prenylamine or p-chlorophenylalanine and adrenocortical activation, even at times in which the peak effect of brain amine depletion occurs.3. Restraint stress causes a manifest increase in brain 5-hydroxytryptamine while decreasing the cerebral noradrenaline and dopamine content. This stress strongly stimulates corticosterone secretion by the adrenals.4. A monoamine oxidase inhibitor, nialamide, at a dose which causes an evident increase in brain amine concentrations, does not modify plasma corticosterone. At the same dose it was, furthermore, unable to prevent the adrenocortical stimulation induced by restraint stress.5. Brain amine content does not seem to play an important part in the control of corticotrophin releasing factor in corticotrophin secretion by the pituitary gland. The relationship between hypothalamic monoamines and other neurohumours is discussed.