Eugenio E. Müller

Anoretic effect of lisuride and other ergot derivatives in the rat

Three ergot derivatives, lisuride, lergotrile and bromocriptine, given to rats trained to eat 4 h a day, induced a dose- and time-related anorexia. They were more potent in this context than either amphetamine or fenfluramine. Lisuride and lergotrile failed to increase locomotor activity or to induce stereotyped behaviour at doses corresponding to the ID50 on food intake. At this dose, bromocriptine slightly stimulated motor activity. The anorectic effect of the three compounds was selectively antagonized by blockers of dopamine (DA) receptors in the central nervous system but not by either inhibiton of catecholamine synthesis or blockade of alpha- or beta-adrenoceptors or of serotonergic receptors. Also two blockers of peripheral DA receptors failed to antagonize ergoline-induced anorexia. These findings indicate that stimulation of DA receptors involved in feeding behaviour was responsible for the anorexigenic effect of the ergot derivatives investigated. In most instances this effect occurred at dose levels which failed to induce central stimulant effects.

Mechanisms underlying the prolactin-lowering effect of metergoline in the rat

Abstract Metergoline (MCE), an ergoline derivative with anti-serotoninergic activity was used in rats to determine its effect on the release of prolactin (PRL) and, possibly, the mechanism(s) of this neuroendocrine effect. MCE given by oral, intraperitoneal or subcutaneous route to reserpinized male and female rats proved to be an effective and long-lasting anti-prolactin agent. MCE lowered PRL in hypophysectomized (hypox) rats bearing an ectopic anterior pituitary (AP) when administered parenterally but was completely ineffective when administered orally. In rats with CNS-AP disconnection, blockade of pituitary dopamine (DA) receptors by pimozide completely prevented the PRL-lowering effect of parenterally administered MCE, whereas treatment with 5-hydroxytryptophan (5- HTP) did not impair the effect of MCE on PRL release. In intact male rats, oral administration of MCE completely antagonized the PRL-releasing effect of quipazine and 5-HTP, stimuli which activate the serotoninergic system. MCE slightly inhibited PRL release from AP fragments in vitro .

Effect of hyperprolactinemia and 2-BR-α-ergocryptine on neuroendocrine mechanism(s) for gonadotropin control

Abstract The effect of hyperprolactinemia and of chronic treatment with 2-Br-α-ergocryptine (CB 154, 2.5 mg/kg s c, b.i.d., for 90 days) on hypothalamic centers for gonadotropin control was studied in intact or castrated (CX) Wistar/Furth (W/Fu) rats bearing a PRL-secreting tumor (MtTW5). CB 154 impeded the development of larger tumors in intact male and CX female rats but was ineffective in intact female and CX male rats. Irrespective of CB 154 treatment, plasma PRL at the end of the experiments was in the μg/ml range in all groups. Hypothalamic LH-RH in intact diluent-treated rats was significantly higher than in intact W/Fu controls (non tumor-bearing rats); castration completely antagonized the increased LH-RH content in the W/Fu male rats but was ineffective to modify the increased LH-RH content in the W/Fu female rats. CB 154 markedly decreased LH-RH content in W/Fu male controls, W/Fu male rats and in W/Fu intact and CX female rats. It was ineffective in CX W/Fu male rats and in the cycling W/Fu female controls. These data indicate that: 1) hyperprolactinemia increases hypothalamic LH-RH stores and blocks the discharge of LH-RH which follows castration; 2) CB 154 restores to normal the increased hypothalamic LH-RH stores of hyperprolactinemic rats, likely by promoting LH-RH discharge from the hypothalamus; 3) estrogens seem to counteract the effect of CB 154 on tumor growth.

Stimulation of growth hormone release by luteinizing hormone-releasing hormone and melanocyte-stimulating hormone-release inhibiting hormone in the hypophysectomized rat bearing an ectopic pituitary.

Intrajugular administration of LHRH (0.6 and 1.2 μg) in hypophysectomized rats which received renal grafts of anterior pituitary induced a small but significant rise in plasma GH 5 and 10 min post‐treatment. LHRH, at the same dose levels, was ineffective in weight‐matched intact controls. MIF, at the dose of 1.2 μg, induced a slight GH rise 5 min after treatment in hypophysectomized‐transplanted rats, while it was ineffective in intact controls. Unlike the two hypothalamic peptides, α‐MSH (0.6 and 1.2 μg) was ineffective as a GH‐releaser in both transplanted and intact rats.

Pituitary Hormones and Ergot Alkaloids

From the data presented it appears that ergot drugs are both a useful tool for use in the study of neuroendocrine control of pituitary hormone secretion and a valid pharmacologic weapon for treatment of hyperprolactinemic states, GH and, probably, ACTH and MSH hypersecretion. In fact, they are capable of a long-lasting disruption of PRL secretion from a normal or tumoral pituitary gland, are unable to affect directly the somatotrophs of an intact AP, but inhibit GH and, possibly, ACTH secretion from a hyperplastic or tumoral gland. Ergolines also exert clear-cut PRL-lowering effects and are capable of suppressing GH secretion in acromegaly. The intimate mechanism(s) and hence site(s) of action of some of these compounds await clarification.

Release of Growth Hormone by TRH in Intact Rats or in Intact or Hypophysectomized Rats bearing a Heterotopic Pituitary

Summary Thyrotropin-releasing hormone (TRH) was administered iv using ure-thane anesthesia to either intact female and male controls or intact (IT) or hypophysec-tomized (HT) rats of both sexes bearing an anterior pituitary (AP) graft under the kidney capsule. TRH at all the doses used (0.15, 0.6, and 1.2 μg) elicited a clear GH rise in both IT and HT rats, while only at the highest does (1.2 μg) was it effective in intact controls. Qualitative and quantitative electron microscopic studies performed on the in situ and ectopic pituitaries from IT female rats demonstrated that TRH stimulated exocytosis from the ectopic pituitary at all doses used, whereas only the highest TRH dose was capable of increasing the frequency of exocytosis from the pituitary in situ. The similar responsiveness to TRH of the ectopic pituitary irrespective of the presence of an in situ AP, rules out the possibility that peripheral hormonal factors (e.g., lack of estrogens or thyroid hormones) may play a crucial role in the preferential GH response to TRH present in HT rats.

Brain serotonin turnover in the hypophysectomized rat.

Summary Brain serotonin turnover, as measured from the rate of decline of 5-hydroxyindoleacetic acid after pargyline administration, was higher in hypophysectomized rats than in intact age-matched controls. As a consequence brain 5-HIAA concentrations were also increased after hypophysectomy. The increased brain 5-HT turnover was neither dependent on the duration of hormonal deprivation nor it was related to the extent of sexual maturation of the animal when the pituitary ablation was performed. The finding that hypophysectomy markedly affected the disposal of tryptophan both in the plasma and the brain suggest that the increased brain 5-HT turnover found in hypophysectomized rats may be ascribed to an enhanced availability of this amino acid by brain 5-HT neurons.