Acute effects of para-chloroamphetamine on testosterone and markers of apoptosis in seminiferous epithelium of prepubertal male rats.

Serotonin is a neurotransmitter that affects the secretion of gonadotropins and testosterone. In prepubertal male rats, serotonin has a stimulating role in testosterone secretion. Here, we used prepubertal male rats to study the effects of para-chloroamphetamine (pCA) on circulating testosterone and gonadotropins and markers of apoptosis in germ cells from day 1 to day 5 post-treatment. The intraperitoneal administration of pCA induced a significant reduction in concentrations of hypothalamic serotonin and circulating testosterone, but gonadotropins were not affected. In the seminiferous epithelium of pCA-treated rats, increased the number of germ cells positive to markers of apoptosis, concomitantly with alterations in morphometry and the presence of multinucleated germ cells. Levels of testosterone were reduced starting from 1 day after pCA was administered. The time window between the administration of the pCA and collection of samples was sufficient to detect changes in testosterone levels, in contrast with a previous work where no changes were found. There was a possible relationship between the reduction of testosterone and an increase in the number of germ cells positive to apoptosis markers. However, the mechanism that links pCA-testosterone-germ cell positive to markers of apoptosis is unknown. Our outcomes support the view that pCA exposure during the prepubertal stage has an acute impact on testosterone levels and affects the structure and physiology of seminiferous epithelium.

p-Chloroamphetamine decreases serotonin and induces apoptosis in granulosa cells and follicular atresia in prepubertal female rats.

Amphetamine derivatives negatively impact serotonin (5-HT) production, which triggers apoptosis in different tissues, depending on the receptor they bind. 5-HT in the ovary stimulates estradiol secretion, a survival factor of granulosa cells. The effect of amphetamine derivatives on the serotonergic system of the ovary and follicular development is unknown. Therefore, in this study, we investigated the effects of p-chloroamphetamine (pCA), derived from amphetamines, on estradiol production, follicular development, apoptosis of granulosa cells, and serotonin 5-HT7 receptor (R5-HT7) expression. Female rats (30 days old) were injected with 10 mg/kg of pCA intraperitoneally and were euthanized 48 or 120 h after treatment. The concentration of 5-HT in the hypothalamus decreased at 48 and 120 h after treatment and in the ovary at 120 h. The serum concentration of estradiol decreased at all times studied. Follicular atresia, TUNEL-positive (apoptotic) granulosa cells and Bax expression were elevated by pCA, but none of these effects was associated with R5-HT7 expression. These results suggest that pCA induces the dysregulation of the serotonergic system in the hypothalamus and the ovary, negatively impacting estradiol production and follicular development.

Inhibition of serotonin reuptake in the prepubertal rat ovary by fluoxetine and effects on ovarian functions.

Fluoxetine (FLX), a selective serotonin reuptake inhibitor is an antidepressant in the treatment of mood disorders. Its impact on reproductive processes is incompletely known. The present study analyzed the reproductive effects of FLX in prepubertal female rats. Two experiments were conducted. First (acute administration), 30-day-old female rats were injected intraperitoneally with 5mg/kg of fluoxetine-hydrochloride, and were terminated 24, 48 or 72h after the treatment. Second (subchronic administration), FLX was injected on days 30-33 of age, and the animals were terminated the day of first estrus. In acute treatment estradiol concentration increased to 72h. In subchronic treatment increased serotonin concentration in ovaries and decreased the number of ova shed. An increase in number of atretic follicles and oocyte fragmentation was observed in these animals. The results suggest that FLX acts on the ovary or hypothalamus-pituitary axis resulting in modifications of the follicular development and ovulation.

Brain serotonin, psychoactive drugs, and effects on reproduction.

Serotonin, a biogenic amine, is present in significant amounts in many structures of the CNS. It is involved in regulation of a wide variety of physiological functions, such as sensory and motor functions, memory, mood, and secretion of hormones including reproductive hormones. It has also been implicated in the etiology of a range of psychiatric disorders such as anxiety, depression, and eating disorders, along with other conditions such as obesity and migraine. While some drugs that affect serotonin, such as fenfluramine and fluoxetine, have been successfully used in treatment of a range of psychiatric diseases, others, such as the amphetamine analogues MDMA and METH, are potent psychostimulant drugs of abuse. Alterations in serotonergic neurons caused by many of these drugs are well characterized; however, little is known about the reproductive consequences of such alterations. This review evaluates the effects of drugs such as MDMA, pCA, fenfluramine, and fluoxetine on serotonergic transmission in the brain, examines the relationships of these drug effects with the neuroendocrine mechanisms modulating reproductive events such as gonadotropin secretion, ovulation, spermatogenesis, and sexual behavior in animal models, and discusses possible reproductive implications of these drugs in humans.

Comparative effects of injecting 5,6-dihydroxytryptamine in the dorsal or medial raphe nuclei on rat puberty.

The role played by the serotoninergic system in the control of puberty onset and first ovulation in rats is studied in this paper by analyzing the effects of injecting the neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) into the dorsal (DRN) or medial (MRN) raphe nucleus of 30-day-old female rats. Complete lesion to the DRN resulted in the blockade of ovulation and a decrease in both the number of ovarian follicles and the serum concentration of follicle stimulating hormone (FSH). This treatment was also found to be associated with an increase in serotoninergic activity in the anterior and medial hypothalami. A lesion to the central portion of the DRN resulted in a significant decrease in the concentration of progesterone in serum and in the number of ova shed by ovulating animals. The lesion to the lateral portion of the DRN did not have an apparent effect on ovulation rate, the number of ova shed, nor in hormone serum concentration. The injection of propranolol to rats with a lesion to the DRN restored ovulation in 73% of treated animals and returned serotoninergic activity in the anterior hypothalamus to levels similar to those of sham-operated animals. In turn, in the medial hypothalamus, the increase in serotoninergic activity was not modified. The results presented herein suggest that serotoninergic inputs to the anterior hypothalamus have a direct influence on gonadotropin secretion and first ovulation, while the noradrenergic innervation exerts an indirect influence.

Ovulatory response to the sequential administtration of follicle stimulating hormone and human chorionic gonadotropin by autografted ovary in unilaterally ovariectomized adult rat with peripheral devervation induced by guanethidine treatment

Ratas hembras adultas con cilos estrales regulares de 4 días de duración fueron unilateralmente ovariectomizadas (se extirpó el ovario derecho) en el día del diestro 1; en el mismo acto, el ovario fue injertado en el tejido celular subcutáneo. Um grupo de estos animales fue inyectado con guanetidina (20 mg/Kg) cada 72 horas, durante 30 días. Todos los animales (tratados o no con guanetidina) fueron autopsiados, en el primer día de estro vaginal luego del período de 30 días. En otro experimento, ratas hemicastradas con auntoinjerto de ovario, tratadas o no con guanetidina como en el experimento anterior, a los 30 días luego de la hemiovariectomia y el autoinjerto, estando en diestro, fueron tratadas con 45 i.u de hormona folículo estimulante ovina (FSH); 56 horas después recibieron 25 u. i. de gonadotropina coriónica humana (hCG) y fueron autopsiadas 20 horas después. Otro grupo de animales con hemicastración y autoinjerto, con o sin tratamiento con guanetidina, en el día treinta del postoperatório, también en diestro, fueron inyectados con 10 ng de benzoato de benzoato de estradiol (BE) y se les autopsió en el primer día de cornificación vaginal que siguió al tratamiento. La tasa de animales ovulantes en el ovario in situ no fue modificada por el tratamiento con guanetidina, FSH y hCG o BE. La administración de guanetidina provocó disminución del número de ovocitos liberados por animal ovulante (8.3 ñ 0.8 vs 10.4 ñ 0.3, - < 0.05) y menor peso final del ovario remanente que en el grupo no tratado (18.8 ñ 0.7 vs 23.7 ñ 0.7, - < 0.01). Aunque el grado de hipertrofia compensadora fue similar en ambos grupos (45.5% y 48.8%). La respuesta ovulatoria (tasa de animales ovulantes y número de ovocitos liberados por animal ovulante) y el aumento del peso del ovario remanente inducidos por la administración de FSH y hCG o de BE, no fueron modificados por el tratamiento previo con guanetidina. El estudio histológico del injerto de ovario realizado en los animales sin tratamiento, o que fueron inyectados con guanetidina, FSH y hCG o benzoato de estradiol, no mostró signos de ovulación...