Effect of Norepinephrine Synthesis Inhibitors and a Dopamine Agonist on Hypothalamic Lh-Rh, Serum Gonadotrophin and Prolactin Levels in Gonadal Steroid Treated Rats

Abstract

The relationship between the medial basal hypothalamus (MBH) LH-RH activity and LH release was studied following progesterone (P) treatment of oestrogen-primed ovariectomized rats (day 0). Following P administration at 10.00 h (day 2) serum LH levels increased rapidly after 13.00 h to peak levels attained at 15.00 h and maintained until 18.00 h. Coincident with the onset of augmented release and peak serum LH concentrations at 15.00 h there was a significant enhancement in the MBH LH-RH activity. Thereafter, the MBH LH-RH stores promptly fell and remained at morning low levels through the rest of the LH surge period. P treatment also stimulated release of FSH and prolactin in the afternoon. Administration of norepinephrine (NE) synthesis inhibitors, diethyldithiocarbamate (DDC) and U-14,624 before P blocked the afternoon increments in serum gonadotrophins and the MBH LH-RH levels; prolactin release was also suppressed in DDC treated rats. In contrast, lergotrile mesylate (dopamine agonist) treatment prior to P administration suppressed only the afternoon increase in prolactin release. These studies show that (1) P can stimulate MBH LH-RH activity in oestrogen-primed rats and these Supported by grant NIH HD 08634. 0 Eli Lily Research Laboratories, Indianapolis, Indiana. effects are transmitted to the LH-RH peptidergic neurons via NE synapses in the preoptic area and (2) a common central NE system may mediate the stimulatory feedback effects of P on gonadotrophin and prolactin release.Administration of progesterone ( ) to oestrogen-primed ovariectomized rats elicits a pro-oestrus-type surge of serum gonadotrophins (Caligaris et al. 1971; Kalra et al. 1972) and prolactin {Caligaris et al. 1974). Several studies have demonstrated that the stimulatory feedback action of on gonadotrophins is mediated primarily by central norepinephrine (NE) systems {Kalra et al. 1972; Kalra l'alia), however, the neurotransmitter(s) involved in prolactin release has not been identified. Besides these information, little is known about the neuro¬ endocrine mechanisms by which progesterone stimulates the secretion of pituitary gonadotrophins and prolactin. In this report we describe (a) the time sequence of changes in hypothalamic LH-RH activity associated with the Pinduced surge of serum LH and (b) the effects of two NE synthesis inhibitors, diethyldithiocarbamate (DDC, Magos 8c Jarvis 1970; Carr et al. 1977) and U-14,624 (l-phenyl-3-(2-thiazolyl)-2 thiourea, Johnson et al. 1970; Khalsa et al.

Effects of Ovarian Hormones on Norepinephrine and Dopamine Turnover in Individual Hypothalamic and Extrahypothalamic Nuclei

“…This may, in turn, stimulate the release of LH and/or PRL via an interaction with other neuronal systems. Such a proposal is consistent with studies showing that noradre nergic antagonists and neurotoxins prevent the stimulatory effects of ovarian hormones on both LH and PRL secretion [5,[16][17][18][19]28].…”

“…Treatment of ovariectomized rats with estrogen also inhibits noradrener gic neurotransmission, as evidenced by decreased turnover of NE in the hypothalamus [1,9, 13]. Administration of nor adrenergic synthesis inhibitors or receptor blockers pre vents the occurrence of the preovulatory LH surge and ovu lation in cycling female rats [18] and abolishes the stimula tory effect of estradiol or progesterone on LH and PRL re lease in ovariectomized, estrogen-primed rats [16,17], ConReceived: April 27, 1981 Accepted after revision: November9, 1981 sistent with these findings, ovariectomy transiently alters hypothalamic NE [1], and the turnover of NE is enhanced in the hypothalamus during proestrus and also after admin istration of progesterone to estrogen-primed rats [13, 24, 26, 34], suggesting increased noradrenergic activity during peri ods of elevated LH and PRL secretion.These results suggest that the inhibitory feedback actions of estradiol on LH may involve, in part, the suppression of central noradrenergic neurotransmission, while the stimula tory feedback actions of ovarian hormones on LH and PRL release may be mediated by enhanced noradrenergic trans mission. NE systems may, in turn, regulate the secretion of LH-releasing hormone [27, 28], as well as other systems (e.g.…”

Effect with time of a norepinephrine synthesis inhibitor (U-14,624) on hypothalamic catecholamine and plasma gonadotrophin concentrations in the ovariectomized rat

“…Specific catecholamine synthesis inhibitors have been used to investigate the relationship between these neurotransmitters and pituitary gonadotrophin release (Coppola, Leonardi & Lippman, 1966;Kalra, Kalra, Chen & Clemens, 1978;Weiner & Ganong, 1978). 1-Phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624), which acts upon dopamine-ß-hydroxylase to prevent norepinephrine synthesis from its precursor dopamine, is one such drug whose effects have been extensively studied (Johnson, Boukma & Kim, 1970; Kalra & McCann, 1973; Drouva & Gallo, 1976;Kalra, 1977;Kalra et al, 1978).…”

“…1-Phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624), which acts upon dopamine-ß-hydroxylase to prevent norepinephrine synthesis from its precursor dopamine, is one such drug whose effects have been extensively studied (Johnson, Boukma & Kim, 1970; Kalra & McCann, 1973; Drouva & Gallo, 1976;Kalra, 1977;Kalra et al, 1978). This pharmacological agent suppresses gonadotrophin secretion, implicating norepinephrine as being facilitatory to gonadotrophin release (Drouva & Gallo, 1976;Kalra, 1977;Kalra et al, 1978). However, little is known about the time course of effects of U-14,624 on hypothalamic catecholamines and plasma gonadotrophin levels.…”

Gonadotropin Secretion following Intraventricular Norepinephrine Infusion into Neonatally Androgenized Female Rats

“…Further, the neural trigger for LH secretion ap pears to reside in part within the catecholaminergic system, as it has been demonstrated that the inhibition of catechol amine synthesis will block phasic LH secretion [11][12][13]. In addition, the administration of norepinephrine (NE) [14] and a-adrenergic agonists, but not [1-adrenergic agonists [15] or dopamine [21], into the third ventricle will elicit an immediate rise in plasma LH in the rat.…”