Hyperprolactinemic Male Rats Research Articles

Interaction Among Hormones or Peptides May Be Involved in Gastric Motor Physiology

manuscript, The role of cholecystokinin 1 receptor in prolactin inhibited gastric emptying of male rat, is a well designed study.1 I would like to congratulate the authors for their excellent work. In the acute hyperprolactinemic rats, the authors found that prolactin inhibited the gastric emptying dose-dependently and increased the level of cholecystokinin (CCK). selective CCK1 receptor antagonist restored the delayed gastric emptying induced by prolactin although it had no effect on gastric emptying, which suggested that prolactin worked via the CCK1 receptor. In the chronic hyperprolactinemic rats, similar increase of CCK level and delayed gastric emptying was also found. Previous studies have demonstrated the effect of prolactin on gastrointestinal motility in lactating rodent.2 Increases in gastric emptying and gastrointestinal transit correlated with lactation and plasma prolactin levels. In this study, the inhibited gastric emptying was found in hyperprolactinemic male rats, which suggested that the effect of prolactin differed by gender and species. This result may provide a guide for future study and clinical use. reviewer has some comments: (1) purpose of experiments with chronic hyperprolactinemic rats, I suppose, is to confirm that chronic and exogenous prolactin is also capable of inhibiting the gastric emptying via CCK. However, it has been reported that prolactin can stimulate the secretion of hormones such as testosterone etc.3 It is also demonstrated that the sexual hormones have the ability of regulating the gastric emptying.4,5 Administration of estrogen inhibits the rat gastric emptying while progesterone enhances the gastric emptying. Therefore, a further session including the CCK1 receptor antagonist should be investigated to confirm that the exogenous prolactin also act through the CCK. (2) As the authors mentioned, prolactin showed a reversed effect in lactating rats. For more reliable result presenting different effects of prolactin on gastric emptying in different genders, it is better to perform an additional experiment involving no-lactating female rats since the sexual hormones during lactation are completely different from non-lactating period and the hormones may have effect on gastric emptying, such as progestrone etc.6 (3) CCK is an important hormone for regulating the food intake and satiety sensation.7-9 CCK induces reduction of food intake dose-dependently and CCK1 receptor is involved in regulating caloric intake. In the experiments of chronic hyperprolactinemic rats, the author did not show whether there were any changes in the food intake and weight in the rats or not. If yes, it might enlighten some new use of prolactin, such as in obesity.

Hyperprolactinaemia and cyclosporine treatment on secretion of adenohypophyseal hormones

The possibility of interactions between the effects of cyclosporine (CyA) and prolactin to regulate various physiological functions has been suggested. To further analyze these interactions, the effect of chronic CyA administration on the secretion of adenohypophyseal hormones in hyperprolactinemic male rats, was studied. Male rats were grafted one pituitary gland under the kidney capsule or were sham-operated at 30 days of age. Both pituitary-grafted and sham-operated rats were given s.c. injections of vehicle or CyA (5mg/kg/day) for 30 days beginning on the day of surgery. Pituitary-grafting increased the plasma leveles of prolactin and decreased the plasma levels of luteinizing hormone (LH), whereas growth hormone (GH), thyroid stimulating hormone (TSH) and follicle stimulating hormone (FSH) did not change. CyA treatment to sham-operated rats did not modify plasma prolactin levels and decreased plasma levels of GH and LH. Administration of the immunosuppressor to pituitary-grafted rats decreased plasma prolactin levels and augmented plasma levels of LH and FSH. Plasma TSH levels did not change after CyA treatment either in sham-operated or in pituitary-grafted rats. These data suggest that CyA may modify the effects induced by prolactin on pituitary hormone secretion, although direct effects of the drug on the hypothalamic-pituitary axis cannot be excluded, according to the data obtained in sham-operated rats.

Effects of cyclosporin treatment on prolactin pulsatility in chronic hyperprolactinemic male rats

Neuroendocrine effects of cyclosporin (CsA) have been demonstrated, but the mechanisms involved are poorly understood. This work was designed to analyse (i) if chronic CsA administration could influence the episodic secretion of prolactin in adult male rats; and (ii) the effects of the chronic administration of the drug, in adult animals with elevated plasma prolactin levels. Male rats were implanted with one anterior pituitary gland under the kidney capsule or were sham-operated, at 30 days of age. Both pituitary-grafted and sham-operated rats were injected subcutaneously with vehicle or CsA (5 mg/kg/day) for 9 days beginning at the 60th day of age. In pituitary-grafted male rats, mean prolactin levels, absolute prolactin pulse amplitude and mean half-life of the hormone increased, while the pulse frequency and relative amplitude of the peaks decreased, as compared with sham-operated rats. CsA administration to sham-operated rats decreased the relative pulse amplitude of prolactin but increased the mean half-life of the hormone, the pulse duration and the mean hormone levels, as compared with rats of the same group treated with vehicle. However, CsA treatment to pituitary-grafted rats decreased mean prolactin levels and the absolute amplitude of its peaks and increased the relative amplitude of its pulses, whereas all the other parameters showed no change. When considering circulating values of prolactin in plasma from the trunk blood, CsA administration was followed by changes similar to those described when mean values of the serial samples were considered. These data suggest the existence of an interrelationship between elevated circulating prolactin levels and CsA, which probably takes place at the hypothalamic level, to regulate the pulsatile pattern of prolactin secretion in male rats, although a direct effect of the drug on the ectopic gland in pituitary-grafted male rats cannot be excluded.

Plasma levels of luteinizing hormone during hyperprolactinemia: response to central administration of antagonists of corticotropin-releasing factor.

Since high concentrations of prolactin (PRL) enhance the hypothalamic release of corticotropin-releasing factor (CRF), and CRF decreases the hypothalamic secretion of luteinizing hormone (LH)-releasing hormone (LHRH), it could be that CRF is involved in the suppressed secretion of LH during hyperprolactinemia. The aim of this study was to explore this possibility in hyperprolactinemic male rats. Hyperprolactinemia, induced by insertion of 3 pituitary glands under the kidney capsule, decreased plasma LH levels by 68% and caused a 2-fold increase in plasma corticosterone. Intracisternal administration of the CRF antagonist alpha-helical CRF(9-41) induced both in pituitary-grafted rats and in normoprolactinemic controls a 2 to 3-fold increase of LH in the plasma sample taken 1 h after injection of alpha-helical CRF(9-41). Plasma levels of LH in pituitary-grafted rats were 2-3 times higher during intracerebroventricular infusion for 7 days with CRF antiserum than during saline infusion. Furthermore, after infusion of CRF antiserum for 7 days into the lateral brain ventricle plasma LH levels had increased by 270% in normoprolactinemic male rats. These results indicate that hypothalamic CRF is involved in the control of LH release in male rats. To further investigate whether CRF is involved in the effect of PRL on LH secretion, we infused PRL, alone or together with CRF antiserum, for 7 days into the lateral brain ventricle of normoprolactinemic male rats. After 7 days of PRL infusion, LH levels had decreased by 45%, whereas plasma corticosterone was 150% higher. This action of PRL on LH and corticosterone was prevented when besides PRL also CRF antiserum was infused.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of bromocriptine (CB-154) treatment on copulatory behavior in hyperprolactinemic adult male rats.

Adult male rats received pituitary transplantations to induce hyperprolactinemia. Some of those had bromocriptine (CB-154) treatment, and the other had vehicle (saline) as control. The grafted animals with vehicle exhibited significantly more suppression than sham operated animals. While the hyperprolactinemic rats treated with CB-154 showed no significantly more suppression of copulatory behavior than sham operated control. In the grafted animal without CB-154 treatment, the concentration of serum PRL was significantly higher than in sham operated controls. There were no significant differences in adrenal weight and serum levels of gonadotropin between grafted and control groups. These results may imply that PRL has direct actions on central nervous system (CNS) and inhibits copulatory behavior in hyperprolactinemic male rats.

Single Cell Levels of Hypothalamic Messenger Ribonucleic Acid Encoding Luteinizing Hormone Releasing Hormone in Intact, Castrated, and Hyperprolactinemic Male Rats*

We have examined the changes that occur in neuronal expression of LHRH mRNA in response to castration and hyperprolactinemia in male rats. Single cell levels of LHRH mRNA were determined by quantitative in situ hybridization histochemistry using an 35S-labeled synthetic 48-base oligodeoxynucleotide probe and quantitative autoradiography. Nine days postcastration, a 10.4-fold increase in mean plasma LH titers was observed which was associated with significantly increased LHRH mRNA in rostral hypothalamic neuronal cell bodies. Both increases were blocked in rats rendered hyperprolactinemic by the presence of the 7315a PRL-secreting pituitary tumor. The location and number of neurons expressing LHRH mRNA were unchanged, indicating that these differences were attributable to amounts of mRNA expressed per neuron. Experimental differences occurred in LHRH perikarya situated throughout the rostral hypothalamus from the organum vasculosum of the lamina terminalis to the caudal extent of the medial preoptic nucleus. These results suggest that gonadal steroids and PRL are involved, either directly or indirectly, in regulating the biosynthesis of LHRH in the rostral hypothalamus.

Extra-hypothalamic dopamine is not involved in the effects of hyperprolactinemia on male copulatory behavior

Experiments were performed to determine if the inhibition of copulatory behavior observed in male rats with chronically elevated serum prolactin levels (hyperprolactinemia) is associated with changes in central dopaminergic function in the nigrostriatal and mesolimbic systems. Chronic hyperprolactinemia, induced by ectopic pituitary grafts, inhibited sexual activity but was not associated with changes in locomotor activity, stereotyped behavior in response to various doses of apomorphine, or 3H-spiroperidol binding to striatal homogenates. However, open-field defecation was reduced in the pituitary grafted animals. The results of the present study show that changes in nigrostriatal dopamine receptor sensitivity do not contribute to the inhibition of sexual behavior in hyperprolactinemic male rats. In addition, these results also demonstrate that the effects of hyperprolactinemia are relatively specific to copulatory behavior and appear not to involve general behavioral suppression.

The effect of luteinizing hormone releasing hormone on the copulatory behavior of hyperprolactinemic male rats

The present study was undertaken to test the hypothesis that the deficits in copulatory behavior observed in hyperprolactinemic male rats may be related to a reduction in hypothalamic release of luteinizing hormone releasing hormone (LHRH). Adult male Fischer 344 rats were made hyperprolactinemic by ectopic pituitary grafts or were sham operated and 30 min prior to being tested for copulatory performance received a single subcutaneous injection of 500 ng LHRH, 100 ng LHRH, or saline. On different occasions, testosterone (T) levels were measured in plasma collected 30 min following identical treatments. Plasma prolactin (PRL) levels were determined in samples collected 30 min after injection of 500 ng LHRH. Pituitary grafting produced the expected, significant increase in plasma PRL levels and significant deficits in copulatory behavior. Treatment of hyperprolactinemic subjects with 500 ng LHRH significantly reduced both the time to first intromission and the time to ejaculation to times comparable with those of sham-operated subjects. The 100-ng dose produced a significant reduction in mount frequency. Plasma T levels were significantly elevated following either dose of LHRH. These results demonstrate that exogenous LHRH can restore normal copulatory performance in hyperprolactinemic male rats and support the hypothesis that a reduction in hypothalamic LHRH release is responsible for the behavioral deficits observed in those animals.

Hormonal responses to female conspecifics in hyperprolactinemic male rats and mice

Exposure to a female results in an acute release of LH and testosterone (T) in normal male rats and mice. This study was conducted to determine whether these hormonal responses are altered in hyperprolactinemic (hyperPRL) male rats in which copulatory behavior is known to be suppressed and in hyperPRL male mice in which it is not. Adult male CDF (F-344) rats were made hyperPRL either by grafting of three anterior pituitaries under the kidney capsule or by treatment with diethylstilbestrol (DES). Exposure of control males to receptive females for 10–15 min produced the expected two- to fourfold statistically significant elevations in plasma LH levels. In contrast, plasma LH levels in pituitary grafted or DES-treated males were not altered by female exposure. Male mice were pituitary grafted (two pituitaries per recipient) or sham-operated and housed individually with a female for 1 week. The resident females were then replaced with novel females in half of the cages and blood samples were taken from the males after 5 min exposure for determination of LH levels or after 45–60 min exposure for T levels. Female-induced LH and T elevations occurred in both hyperPRL and control groups. Failure of hyperPRL male rats to experience an increase in plasma LH levels in response to a female suggests abnormality of mechanisms controlling LHRH release. Suppression of LHRH release may be involved also in the induction of deficits of sexual behavior in these animals.

Altered sensitivity to an opiate antagonist, naloxone, in hyperprolactinemic male rats.

An increase in endogenous opiatergic tone has been suggested as a mechanism for suppression of gonadotropin release in hyperprolactinemia (hyperPRL). In an attempt to evaluate this possibility in hyperprolactinemic males, we have examined the effects of a specific opiate antagonist, naloxone, on plasma LH levels in adult male rats rendered hyperprolactinemic by transplanting two pituitary glands underneath the kidney capsule. Naloxone was administered intravenously (i.v.) at different dose levels (0.2,2, or 20 mg/kg body weight) and blood samples were collected at intervals ranging from 15 to 60 min after naloxone administration. In all experiments, plasma LH levels in the sham-operated controls were significantly increased after naloxone administration, while those in the pituitary-grafted group remained unaltered. Injecting naloxone daily for 3 or for 10 days failed to alter plasma LH levels in both sham-operated and pituitary-grafted animals. Administration of LHRH induced a 7-fold increase in plasma LH levels in both the pituitary-grafted animals and the sham-operated controls. These studies demonstrate that hyperPRL interferes with the naloxone-induced rise in circulating LH levels in the male rat.

Differential effects of bromocriptine treatment on LH release and copulatory behavior in hyperprolactinemic male rats

Hyperprolactinemia (hyperPRL) induced by grafting four pituitary glands under the kidney capsule suppresses copulatory behavior in male rats and sexually naive male mice. In mice sexual experience attenuates the suppressive effects of hyperPRL on mating behavior, thus a comparison of the behavioral consequences of inducing hyperPRL in sexually naive and experienced male rats was undertaken. Hyperprolactinemia had a significant suppressive effect on mating behavior in both groups of animals. Experienced animals showed deficits in all parameters studied except mount frequency and postejaculatory interval, while naive animals differed from respective controls only in mount latency, intromission latency, and intromission frequency. To determine if the inhibition of chronically elevated prolactin (PRL) levels would reverse the suppression of gonadotropin secretion and copulatory behavior in hyperprolactinemic animals, the effects of bromocriptine (CB-154) administration on plasma hormone levels and mating behavior were examined in pituitary-grafted and control rats. Bromocriptine treatment (1 mg/day for 14 days) led to increases in sexual activity in both the sham-operated and grafted animals. In the grafted animals, plasma PRL was reduced and plasma LH significantly increased in the CB-154-treated animals when compared to oil-treated controls. In sham-operated animals, CB-154 produced no significant changes in plasma LH or FSH despite the suppressed PRL levels. These results indicate that (1) hyperPRL induced by pituitary grafts can cause deficits in mating behavior in male rats despite previous sexual experience, and (2) while CB-154 may be acting through other mechanisms to stimulate copulatory behavior, the reduction of chronically elevated PRL levels due to CB-154 treatment is responsible for reversal of the suppressive effects of hyperPRL on LH secretion.

The effects of elevated circulating prolactin in rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain).

Administration of ovine or rat PRL to animals, including man, has resulted in decreased urine volume and increased urine osmolality. Contamination of PRL preparations with vasopressin is the most likely explanation for the apparent antidiuretic effect. In this study, diabetes insipidus rats lacking vasopressin(homozygous Brattleboro rats) had extra anterior pituitary glands implanted under the kidney capsule, resulting in hyperprolactinemia. The urine of such rats was not more concentrated than that of unoperated littermates or sham-operated littermates with diabetes insipidus. In fact, hyperprolactinemic male rats produced even less concentrated urine than control rats. Furthermore, the hyperprolactinemic rats responded to exogenous vasopressin in a manner similar to normoprolactinemic rats. These studies provide strong evidence against an antidiuretic action of PRL in mammals.