ly-53857 and 6-chloro-2-(1-piperazinyl)pyrazine

Adult Wistar male rats in a thyrotoxic state T4 increases rats) induced by administration of T4 (350 micrograms/kg/day, i.p. for 7 days) as well as their euthyroid controls were submitted to immobilization stress during forty minutes. Prolactin (PRL) secretion during stress was significantly lower in T4 increases rats as compared to control animals. Treatment with MK 212, a serotoninergic agonist, entirely reverts this situation. The effect of MK 212 seems to be due to its interaction with 5-HT2 receptors since it is blocked by LY 53857, a selective 5-HT2 antagonist. Furthermore, the blockade of 5-HT2 receptors by LY 53857, a selective 5-HT2 antagonist, significantly diminishes prolactin (PRL) response to stress in euthyroid rats but has no effect in T4 increases animals. It is suggested that an increased concentration of thyroid hormone in plasma disrupts an endogenous serotoninergic brain input necessary to trigger stress-induced PRL rise.

Topics: Animals; Ergolines; Immobilization; Male; Prolactin; Pyrazines; Rats; Rats, Wistar; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Stress, Psychological; Thyrotoxicosis; Thyrotropin; Thyroxine

Thyroidectomized (TX) adult Wistar male rats and their sham-operated controls were submitted to immobilization stress during forty minutes. Thyroidectomy partially blocks stress-induced prolactin (PRL) secretion. Previous administration of MK 212, a serotonin agonist, reverts this picture. The effect of MK 212 is specifically due to its interaction with 5HT2 receptors, since the injection of LY 53857, a selective blocker of these receptors, 30 min before MK 212, prevents the effect of this serotonin agonist. LY 53857, injected alone, yields a partial blockade of PRL secretion during stress in sham-operated rats. TX rats receiving LY 53857 or saline have comparable low values of plasma PRL during stress. It is suggested that thyroidectomy disrupts the functional integrity of the central serotonergic pathways involved in the stress-induced PRL rise.

Topics: Animals; Central Nervous System; Ergolines; Kinetics; Male; Prolactin; Pyrazines; Radioimmunoassay; Rats; Rats, Wistar; Restraint, Physical; Serotonin; Serotonin Antagonists; Stress, Psychological; Thyroidectomy; Time Factors

The present study was undertaken to determine the involvement of serotonergic 5-HT1 and 5-HT2 receptor subtypes in stimulation of the secretion of prolactin. Several 5-HT agonists were administered, in a dose-response fashion, to conscious rats and the effect on the levels of prolactin in plasma was measured. The 5-HT1A + 5-HT1B agonist RU 24969 (5-methoxy-3[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole succinate) and the 5-HT1 + 5-HT2 agonist MK-212 (6-chloro-2-[1-piperazinyl]pirazine) increased levels of prolactin in plasma in a dose-dependent manner. In contrast, the selective 5-HT1A agonists 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino]tetralin) and ipsapirone (2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3 -(2H) one-1,1-dioxidehydrochloride) did not increase levels of prolactin in plasma at any dose. The 5-HT-releasing drug, fenfluramine, also increased the concentration of prolactin in plasma. Pretreatment with the selective 5-HT2 antagonist, LY53857 (6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid, 2-hydroxy-1-methyl propyl ester (Z)-2-butenedioate [1:1]), did not significantly diminish an increase in levels of prolactin in plasma, induced by injection of fenfluramine. The antagonist LY53857 inhibited, but did not block the MK-212- and RU 24969-induced increase in the levels of prolactin in plasma. By deduction, these data suggest that 5-HT1B receptors, or as yet undefined 5-HT receptor subtypes may be involved in the stimulation of the secretion of prolactin by endogenously released 5-HT, and that 5-HT2 receptors may play a minor role in the serotonergic regulation of the secretion of prolactin.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Ergolines; Fenfluramine; Indoles; Male; Prolactin; Pyrazines; Radioimmunoassay; Rats; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes

In this study we have evaluated a possible role for brain serotoninergic neurons in the regulation of vasopressin secretion using pharmacological methods. In order to accomplish this, we have developed a specific and sensitive vasopressin radioimmunoassay along with a highly reproducible plasma extraction protocol. These tools were used to evaluate the plasma vasopressin response to several pharmacological challenges in conscious rats. Treatment with the serotonin (5-HT) releaser p-chloroamphetamine caused a significant increase in plasma vasopressin concentration. This effect was blocked by posterior hypothalamic deafferentation which separates serotonin cell bodies in the midbrain from their nerve terminals in the hypothalamus. Administration of graded doses of several 5-HT agonists had no effect. However, treatment with MK212, a serotonin agonist with 5-HT1 + 5-HT2 activity, induced a significant increase in plasma vasopressin concentration. The effect of MK212 on plasma vasopressin was completely abolished by the selective 5-HT2 receptor blocker LY53857. These studies confirm and extend studies by others that provide pharmacological evidence for serotoninergic regulation of vasopressin secretion via a selective 5-HT2 receptor mechanism. The specific neuroanatomical site(s) where serotonin exerts this effect are unknown, and the physiological consequences of these studies remain to be established.

Topics: Amphetamines; Animals; Dose-Response Relationship, Drug; Ergolines; Hypothalamic Area, Lateral; Male; p-Chloroamphetamine; Pyrazines; Radioimmunoassay; Rats; Receptors, Serotonin; Serotonin; Vasopressins

The present study was designed to investigate the effect of distinct serotonin (5-HT1A and 5-HT2) agonists and antagonists on renin and corticosterone secretion. Low doses of the selective 5-HT1A agonists 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) (5.0-500.0 micrograms/kg, i.p.) and ipsapirone (TVX Q 7821; 0.5-2.5 mg/kg, i.p.), and of the 5-hydroxytryptamine (5-HT) agonist MK-212 (2.0 mg/kg, i.p.), did not elevate plasma renin activity (PRA) and concentration (PRC) 30 min postinjection. Administration of a higher dose of MK-212 (10.0 mg/kg, i.p.) and of higher doses of ipsapirone (5.0-10.0 mg/kg, i.p.), as well as the 5-HT releaser, fenfluramine (5.0 mg/kg, i.p.), resulted in large increases in PRA and PRC. The effects of MK-212 and fenfluramine on PRA and PRC were blocked by pretreatment with the selective 5-HT2 antagonist, LY53857, in a dose-dependent (0.3-1.0 mg/kg, i.p.) manner. LY53857 (1.0 mg/kg, i.p.) by itself did not affect PRA or PRC. LY53857, furthermore, unmasked a renin-suppressive effect of MK-212, since injection of MK-212 (10.0 mg/kg, i.p.) following LY53857 administration led to a reduction in PRA and PRC. MK-212 (2.0 and 10.0 mg/kg), the high doses of 8-OH-DPAT (500.0 micrograms/kg), ipsapirone (1.0-10.0 mg/kg), and fenfluramine (5.0 mg/kg) all produced an increase in plasma corticosterone levels. The effects of MK-212 and fenfluramine on corticosterone were not inhibited by pretreatment with LY53857. These data suggest that 5-HT1A receptors do not play a role in the regulation of renin secretion, whereas stimulation of 5-HT2 receptors enhances renin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Corticosterone; Ergolines; Fenfluramine; Male; Pyrazines; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Renin; Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes