Stimulatory Effects of 5HT_1A Receptor Agonists on Luteinizing Hormone-Releasing Hormone Release from Cultured Fetal Rat Hypothalamic Cells: Interactions with Progesterone

Abstract

Previous works have suggested an interactive stimulatory effect of progesterone (P) and serotonin (5-HT) on luteinizing hormone release. The purpose of the present study was to determine whether 5-HT via 5-HT_1A receptors interacts with P in the process of luteinizing hormone-releasing hormone (LHRH) release. Using fetal hypothalamic neurons in primary cell cultures the first goal of this study was to determine the effects of 5-HT_1A receptor agonists on LHRH secretion. 8-Hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) or ipsapirone (10^–5M) significantly stimulated LHRH release. Pharmacological studies have allowed to rule out the possible involvement of α₂-or β-adrenore-ceptors, or 5-HT uptake sites, in the stimulatory effect of 8-OH-DPAT on LHRH release, thus demonstrating the specific involvement of 5-HT_1A receptors in the stimulation of LHRH release. The second goal was to test the ability of P to stimulate LHRH release from fetal hypothalamic neurons. P (10^–6M) applied for 30 or 120 min significantly stimulated LHRH secretion. The maintenance of the stimulation of LHRH release by P after a cycloheximide treatment or by an impermeable analog of P, P-3-BSA, has suggested a nonge-nomic effect of P on LHRH release. The effects of a pretreatment of cells by P on 8-OH-DPAT-induced LHRH release were tested. While 10^–7M P alone did not stimulate LHRH release, this concentration of steroid potentiated the LHRH response to 10^–5M 8-OH-DPAT. These findings led to the conclusion that P acting at the level of the plasma membrane potentiates the stimulatory effect of 5-HT_1A receptor agonists on LHRH release.

Sex Hormones and Mood in the Perimenopause

“…20) experimental paradigms, estradiol has been observed to inhibit serotonin transporter (SERT) mRNA, 21 alter SERT protein levels and binding, 20–25 increase 5‐HT2A receptor binding 26 and mRNA, 27 and facilitate imipramine‐induced downregulation of 5‐HT2 receptors in the rat frontal cortex, an action seen to accompany antidepressant administration 28 . Although, 5HT 1A receptor binding is modulated by both estradiol 29–35 and progesterone, 25,36–38 estradiol has been reported to both decrease activity of the 5HT 1A receptor (downregulation and uncoupling from its G‐protein) 39,40 and increase the expression of 5HT 1A receptors. The latter action occurs by means of an interaction involving nuclear factor‐κB complexes, estrogen‐receptor‐α and a nonclassical estrogen response element 30 …”

Influence of Serotonin on the Development and Migration of Gonadotropin‐Releasing Hormone Neurones in Rat Foetuses

“…It is difficult to interpret the finding of the regional specificity of the 5-HT action on differentiating GnRH neurones because there is no gradient in 5-HT content in the forebrain. The mechanism of sexual dimorphism of GnRH neurone reaction to 5-HT is also far from understood, although it might be a result of the modulation of 5-HT receptors by sex steroids, as in adulthood (49).…”

Serotonin Inhibits Luteinizing Hormone Release via 5-HT1A Receptors in the Zona incerta of Ovariectomised, Anaesthetised Rats Primed with Steroids

“…This is based on a wide variety of experiments including electrical stimulation and lesions of the DRN [17, 21]and noting a positive correlation in 5-HT activity and LH release in the three areas mentioned above (DRN, POA and ME) in both intact proestrous rats and ovariectomised rats primed with gonadal steroids that induce an LH surge (DRN [22, 23]; POA [19, 23, 24]; ME [25, 26]). Pharmacological evidence in vivo [28, 29]and in vitro [30, 31]also supports the stimulatory role of 5-HT in regulating LH release. The in vivo experiments indicate that 5-HT acts via 5-HT2 receptors to stimulate the pre-ovulatory LH surge [28, 29, 32, 33].…”

“…The in vivo experiments indicate that 5-HT acts via 5-HT2 receptors to stimulate the pre-ovulatory LH surge [28, 29, 32, 33]. The in vitro experiments show that the positive feedback effect of P may be mediated by 5-HT1A activity [31, 34, 35]. …”

“…Based on the use of selective antagonists in some of these experiments it has been suggested that the inhibitory effects are mediated by 5-HT2 receptors [42]. It seems, therefore, that the stimulatory and inhibitory effects of 5-HT both involve 5-HT2 receptors: the possibility that 5-HT1A receptors mediate an inhibitory as well as a stimulatory effect (as noted in vitro [31]) has not been shown so far.…”