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Breastfeeding deficiency in the early postnatal period can lead to metabolic and hormonal disorders in adulthood. However, there are no studies on the effect of starvation in early ontogeny on metabolic and hormonal parameters in aging animals. The effect of such starvation on the functions of the endocrine system has not been practically studied. The aim of this work was to study how interruption of lactation in lactating female rats (19-21 days of postnatal development of rat pups) affects metabolic parameters, glucose tolerance, insulin sensitivity, and hormonal status of the gonadal and thyroid axes in their offspring, 18-month-old male rats. Inhibition of lactation was induced by treating female rats with bromocriptine (10 mg/kg/day). It has been shown that aging male rats with partial deprivation of breastfeeding have characteristic signs of the metabolic syndrome, such as the increased body weight and adipose tissue, impaired glucose tolerance, insulin resistance, and hyperleptinemia. They have reduced levels of testosterone and thyroid hormones, increased levels of thyroid-stimulating hormone, reduced steroidogenic response to gonadoliberin and a decrease in thyroliberin stimulating effect on thyroxine levels. Thus, short-term deprivation of breastfeeding caused by bromocriptine-induced inhibition of lactation in lactating females leads to the development of metabolic syndrome and hormonal dysregulation of the reproductive and thyroid systems in 18-month-old male rats.

One of the approaches to correct type 2 diabetes mellitus (T2DM) and its complications is the use of drug bromocryptine mesylate (BCM), a selective agonist of type 2 dopamine receptors (DA2R). At the same time, the efficiency and the mechanisms of action of BCM in treatment of severe forms of T2DM are not currently understood. The objective was to study the effect of four-week treatment of male rats with neonatal T2DM model using BCM (300 mg/kg/day) on their metabolic parameters and activity of the adenylyl cyclase signaling system (ACSS) in the hypothalamus. The BCM treatment restored glucose tolerance and its utilization by exogenous insulin, and normalized lipid metabolism by lowering the levels of triglycerides and atherogenic cholesterol increased in T2DM. In the hypothalamus of BCM-treated diabetic rats, the regulation of ACSS by agonists of type 4 melanocortin receptor (MC4R), DA2R and 1B-subtype serotonin receptor, and the expression of Mc4r gene encoding MC4R were restored. Meanwhile, the BCM treatment had no effect on plasma insulin level and insulin production by pancreatic b-cells. The obtained data indicate the significant prospects of BCM to treat severe forms of experimental T2DM, and show that the therapeutic potential of this drug includes its ability to restore the hypothalamic signaling systems sensitive to monoamines and peptide of the melanocortin family, which are responsible for the control of energy metabolism and insulin sensitivity.

One of the common complications of type 2 diabetes mellitus (DM2) are cardiovascular diseases and dysfunctions of the reproductive system, indicating the urgency of developing new approaches to their correction. Last years for the treatment of DM2 began to use bromocryptine (BC), the agonist of type 2 dopamine receptors, which not only restores the energy metabolism, but also prevents the development of cardiovascular diseases. However, the mechanisms and targets of BC action are poorly understood. The purpose of this study was to investigate the effect of BC treatment on functional activity of adenylyl cyclase signaling system (ACSS) in the myocardium and testes of male rats with DM2, which is caused by high-fat diet and treatment with streptozotocin (25 mg/kg). The treatment with BC (60 days, orally at a dose of 0.6 mg/kg once every two days) was started 90 days after the beginning of high-fat diet. Diabetic rats had an increased body weight, elevated triglycerides level, impaired glucose tolerance, and insulin resistance. The treatment with BC resulted in the restoration of glycometabolic indicators and in the improvement of insulin sensitivity. Adenylyl cyclase (AC) stimulating effects of guanylylimidodiphosphate (GppNHp), relaxin, and agonists of β-adrenergic receptors (β3-AR)--isoproterenol and norepinephrine were decreased in the miocardium of the diabetic rats. The corresponding effects of the β-agonists BRL-37344 and CL-316243 was preserved. The inhibitory effect of somatostatin on forskolin-stimulated AC activity was attenuated, while the inhibitory effect of noradrenaline mediated through α2-AR increased. The treatment with BC resulted in the normalization of the adrenergic signaling in the myocardium and partially restoration of AC effects of relaxin and somatostatin. In the testes of diabetic rats, the basal and stimulated by GppNHp, forskolin, human chorionic gonadotropin and pituitary AC-activating polypeptide AC activity were decreased, and the inhibitory effect of somatostatin was attenuated. The changes in testicular ACSS in the case of BC treatment were weakly expressed. Thus, long-term BC treatment restores the functional activity of ACSS in the myocardium and testes of diabetic rats that underlies the therapeutic effect of BC on functions of the cardiovascular and reproductive systems disturbed in DM2 and should be considered when developing strategies for treatment type 2 diabetes and its complications.

In the myocardium and skeletal muscles of rats deprived of food for 2 days, basal activity of adenylate cyclase decreased, while the sensitivity of adenylate cyclase signaling system to the stimulating effects of non-hormonal agents (guanine nucleotides and NaF) and beta-agonist isoproterinol modulating adenylate cyclase through stimulating G proteins increased. In starving organism, the regulatory effects of hormones realizing their effects through inhibitory G proteins (somatostatin in the myocardium and bromocryptin in the brain) weakened. Their inhibitory effects on forskolin-stimulated adenylate cyclase activity and stimulating effects on binding of guanosine triphosphate decreased. In the brain of starving rats, the differences in the sensitivity of the adenylate cyclase signaling system to hormones and nonhormonal agents were less pronounced than in the muscle tissues, which attested to tissue-specific changes in the functional state of this system under conditions of 2-day starvation.

The effectiveness of treatment of hyperprolactinemia (of functional and organic genesis) with dophamin agonists was studied in 97 women aged 18-32. The effectiveness was evaluated by normalization of the laboratory indices of prolactin level, and the clinical parameters: restoration of the regularity of the menstrual cycle; resumption of ovulation; becoming pregnant; stopping of galactorrhea. Dophamin agonists of the I generation, parlodel, and of the III generation, dostinex, were prescribed. The doses were selected individually, in accordance with the monthly indices of the prolactin level. The duration of treatment was 6 months with a subsequent 6-month follow-up. At micro- and macroadenomas of hypophysis, dostinex proved most effective and highly durable. Dostinex is characterized by infrequent occurrence of side effects; is particularly recommended in cases of parlodel resistance or intolerance. Parlodel may be a preparation of choice for treating all kinds of hyperprolactinemia conditions; no contraindication at becoming pregnant.

The development of experimental type II diabetes mellitus in rats was accompanied by dysfunction of inhibitory and stimulatory heterotrimeric G-proteins, components of hormone-sensitive adenylate cyclase signal system. The function of inhibitory G-proteins decreased most significantly under these conditions, which is seen from weakened regulatory effects of somatostatin (in the myocardium) and bromocriptine (in the brain striatum) realized via inhibitory G-proteins in diabetic rats compared to controls. These hormones produce less pronounced inhibitory effect on forskolin-induced activation of adenylate cyclase. In the myocardium of diabetic rats, the stimulatory effects of isoproterenol and relaxin on adenylate cyclase realized via stimulatory G-proteins were decreased to a lesser extent. In the striatum of diabetic rats the stimulatory effect of serotonin and relaxin did not differ from the control. Therefore, dysfunction of stimulatory G-proteins during type II diabetes mellitus is characterized by tissue specificity. Synthetic peptides corresponding to functionally important regions in a-subunits of G-proteins and relaxin receptor LGR7 less effectively inhibited hormone signal transduction via the adenylate cyclase system in rats with type II diabetes. These changes reflect abnormal coupling between receptors and G-proteins in tissues of diabetic rats.

Using the technique of immunohistochemistry in combination with cytophotometry, we have studied the effect of periovulatory hyper- and hypoprolactinemia on the expression of prolactin receptors in various cell types of rat ovaries during early estrus. It has been shown that intense specific staining of oocytes is positively controlled by prolactin. The maximal intensity of specific staining was found in cells of the cumulus and the inner layer of granulosa cells in mature follicles; staining intensity gradually diminished towards the outer boundary cell layer. Postovulatory follicles are distinct from those mature follicles in which there was no ovulation in their more intense manifestation of prolactin receptors in cells of the inner layer and cumulus, as well as in increased positive staining (after prolactin administration) only in the granulosa layer cells closest to theca. In follicles which did not ovulate by the time of the early estrus, prolactin administration leads to a proportional growth of specific immunoreactivity in all cell layers of the granulosa. The administration of bromocryptin, an inhibitor of prolactin secretion, leading to a 10-fold decrease in prolactin level in blood, results in a twofold decrease in the intensity of specific staining of all cell layers of the granulosa in either type of follicle. Corpora lutea of the previous cycle have irregularly positioned luteocytes with weak and strong specific staining, the intensity of which is not changed in response to prolactin and diminishes slightly after the administration of bromocryptin. We conclude that the most intense changes in the content of prolactin receptors under the conditions of imbalance of this hormone during the periovulatory period are observed in those follicles where the oocyte did not ovulate by the time of early estrus.

The effects of intraperitoneal injections of sulpiride (10 mg/kg), bromocriptine (5 mg/kg), and alaptide (1 mg/kg) on the behavior of male C57BL/6J (C57BL) and DBA/2J (DBA) mice in the open-field test were studied. In this test, C57BL mice exhibited a significantly higher horizontal locomotor activity than DBA mice, whereas DBA mice moved in place substantially longer than C57BL mice. Dopaminergic agents had different effects on the open-field behavior in different mouse strains. Alaptide increased horizontal locomotor activity in DBA, but not in C57BL mice; all the three agents decreased the duration of movement in place in DBA but not in C57BL mice; bromocriptine suppressed vertical locomotor activity and the act of looking into holes in C57BL but not in DBA mice. Thus, interstrain differences in dopaminergic functions were demonstrated. The revealed strain-specific characteristics largely contribute to the determination of open-field behavior in the studied mouse strains.

The sensitivity of hypothalamic dopaminergic D2-receptors was studied in 52 patients with various spinocerebellar degenerations (SCD). Radioimmunoassay of blood prolactin enabled the state of these receptors to be evaluated before and after loading with D2-receptor agonist (bromocriptine) and antagonist (metoclopramide). In all forms of SCD, the rate of blood prolactin decrease in response to bromocriptine, was significantly lower than control values, which demonstrated the lower sensitivity of D2-receptors in the hypothalamic tubero-infundibular region to agonists. Metoclopramide caused a higher increase in blood prolactin levels than in the controls. The findings suggest that the state of the receptors was altered in SCD patients. A relationship between the impairments found and the clinical and morphological manifestations of different SCD forms is discussed.

Experiments with primary cultures demonstrated a stimulating effect of TRF on somatotropic hormone (STH) secretion by hypophyseocytes of neonatal but not adult rats and a reduced reactivity of neonatal somatotrophs to the inhibitory effect of somatostatin during short-term incubation. No noticeable serotonin effect on STH release from hypophyseal cells of animals of various ages was observed. During prolonged (24 h) incubation a weak inhibitory effect of bromocriptine and melatonin on STH secretion by pituitary cells of neonatal but not adult rats was observed. These results permit us propose a similarity of the functional characteristics of neonatal pituitary somatotrophs to somatomammotroph properties.

The experiments were made in rats with unilateral lesion to the nigrostriatal tract, which was induced by the highly active dopaminergic neurotoxin 1-methyl-4-phenyl-pyridinium. The rotational activity of rats was evaluated after intragastric and subcutaneous bromocryptine given in a single dose of 10 mg/kg and 25 mg/kg one, two, three and four times. The highest effect of the drug was seen when it was used in the maximum dose of 25 mg/kg, but when the agent is repeatedly given in the above dose, it failed to enhance the rotational activity of rats. The findings may provide evidence for possibilities of increasing the doses of bromocryptine in practical medicine, and for designing the injectable dosage form of the drug.

Age-related peculiarities of the bromocriptine and melatonin effect on macromolecule biosyntheses in cultured rat pituitary cells were studied during long-term (3 day) incubation. Bromocriptine (10(-9)-10(-7) M) caused dose-dependent inhibition of DNA synthesis in pituitary cells of neonatal rats, but only in maximal dose (10(-7) M) it decreased significantly this parameter in pituitary cells of adult animals. Melatonin (10(-8)-10(-6) M) caused significant inhibition of DNA synthesis in cultured cells of neonatal rat pituitaries. However, melatonin did not change DNA biosynthesis in pituitary cells of adult rats. The results obtained permit us to suggest certain contribution of dopaminergic tone and melatonin to the control of proliferative activity of rat pituitary in neonatal period of development.

Puberty was found to be delayed in female rats who had not obtained necessary amount of prolactin with the mother's milk. These rats developed hyperprolactinemia in reproductive age associated with a decrease in the hypothalamus' dopaminergic tonus as well as a decrease of the sexual steroids level. These rats develop most often disorders of estrous cycle and reproductive function.

In experiments on rats which consumed for a long time morphine solution as a drinking liquid there was studied the effect of low doses of bromocriptine on the behavioural manifestations of morphine abstinence syndrome and the condition of the noradrenergic, dopaminergic and conjugated GABAergic systems of the brain. It was shown that the preliminary administration of bromocriptine decreased the degree of the withdrawal syndrome that correlated with the restoration of dopamine content and the normalization of the condition of D2-dopaminergic receptors in different regions of the brain. Bromocriptine exerted no influence on the morphine withdrawal-induced changes in the condition of GABA receptors of the cerebral cortex.

Effects of bromocriptine on hemodynamics and catecholamine exchange were evaluated in patients with borderline arterial hypertension with respect to their family history. The agent was shown to be able to bring down blood pressure and decrease plasma catecholamine levels. With this, platelet monoamine oxidase activity was increased in persons with a family history of hypertensive disease.

A study was made of the influence of agonists and antagonists of catecholamine action on LH and FSH secretion during the second rise of FSH secretion at the early hours of the estrous stage (E). Administration of phentolamine (a blocker of alpha-adrenoceptors) did not change the level of gonadotropins. On the contrary, haloperidol (a blocker of dopamine receptors) lowered the level of FSH at 3 o'clock of the estrous stage but made no effect on the blood concentration of LH. Administration of a stimulator of dopamine receptors increased the blood concentration of FSH at 1 and 3 o'clock of the estrous stage. Acute administration of haloperidol decreased the number of nuclear estradiol-binding sites in the adenohypophysis at 3 o'clock of the estrous stage but did not change the concentration of nuclear receptors of testosterone at either of the above time intervals. The results suggest that estrogenic and androgenic receptors and dopamine cerebral systems are involved in the stimulation of the second wave of FSH secretion. The interrelation of the dopamine activity and level of hypophyseal estradiol receptors, influencing FSH secretion in the early estrus, was established.

Pharmacological analysis of the role of hyperprolactinemia in the pathogenesis of anovulatory syndrome (AS) was performed in neonatally androgenized rats. Dopamine agonist, bromocriptine, administered to I or 2.5 month-old rats for 15 days decreased prolactin content in the adenohypophysis and partially normalized progesterone level in blood plasma. However, bromocriptine failed to prevent the development of AS or to interrupt persistent estrus in neonatally androgenized females. The results are in keeping with the concept on the leading role of hypothalamus noradrenergic insufficiency in the pathogenesis of experimental AS.

Synthetic steroid compounds STS 557 and STS 737 administered to ovariectomized rats increased prolactin secretion to a lesser extent than estradiol benzoate or estrogen J 271. When injected to estradiol benzoate treated ovariectomized rats, compounds STS 557, STS 737 and progesterone failed to change DNA synthesis in the adenohypophysis and prolactin secretion. Only compound STS 737 exerted a pronounced effect on the adenohypophyseal cells in primary cultures. It inhibited DNA synthesis and prolactin secretion. These effects were synergistic with the inhibitory action of bromocriptine (CB-154) that is of certain interest for elaborating methods of treatment of pituitary hyperplasias and tumours.

Effect of dopamine agonist Parlodel in treatment of different types of depressions was investigated. Parlodel was found to have an antidepressant action which enabled to cure some resistant forms of the disease. The positive therapeutic effect of Parlodel resulted in normalization of dopamine metabolism. The drug can be used for treatment of depressions accompanied by dopamine deficiency and resistant to therapy.

Clophelin (CLO) in a dose 10 mg/kg induced aggressive behaviour in mice significantly dependent of genotype. Pretreatment with flupentixol and haloperidol inhibited or blocked CLO-evoked aggression in high-aggressive mice. Apomorphine administered with CLO enhanced aggression in low-aggressive mice. Stimulation of D2 receptors by bromocriptine failed to change CLO-induced aggression. It was suggested that dopamine system was involved in CLO-aggression through D1 receptors.

Correction of behavior of rats preferring for a long time ethanol but not water may be performed using the agents enhancing sexual activity of animals of both sexes: apomorphine (1 mg/kg), bromocriptine (1 mg/kg) and yohimbine (4 mg/kg). Normalization of behavior of the rats manifested by not only a decrease of total ethanol consumption but also by a change of alcohol preference. Bromocriptine exerted the predominant effect on females, and yohimbine on males. Apomorphine was effective in the animals of both sexes but its efficacy was higher in females. The agents produce opposite changes depending on the animal sex in ethanol level during the withdrawal period, the rate of ethanol elimination in the blood at its administration in a test dose and the reaction of self-stimulation of the lateral hypothalamus. Female rats proved to be more sensitive to the drugs' effects related to changes in ethanol metabolism rate. Male animals were more responsive to the effects due to changes in the positive reinforcement system.

Intensity of 3H-dopamine uptake in hypothalamic synaptosomes was similar both in intact rats and in the animals which received a single administration of bromocriptine at a dose of 5 mg/kg within 4 hrs. Within 4 days after the drug administration incorporation of the label was increased 1.22-fold and 1.28-fold in intact and adrenalectomized rats, respectively. Alterations in dopamine uptake in hypothalamic synaptosomes caused by bromocriptine appear to be one of dopaminergic-dependent effects of the drug in the animal brain structures.

The data are presented, obtained in experiments on cyclic female rats. The blood prolactin and luteinizing hormone content was examined and the dopamin level in the preoptic region and mediobasal hypothalamus was determined after a single parlodel injection to animals during the proestrous and/or estrous stage. The most pronounced effect of the drug manifested itself in a decrease in the blood prolactin content, especially in rats within the proestrous stage and, to a lesser degree, during the estrous cycle. An increased dopamin level in the mediobasal hypothalamus and the brain preoptic region of the animals during the proestrous stage was probably secondary. Marked changes in the serotonin levels were not revealed. It is suggested that the relationship between the lactotropic and luteotropic functions of the hypophysis is conditioned, to a considerable extent, by the dopaminergic system of both brain regions, involving in regulation of the gonadotropin secretion. The cyclicity disturbance was not prevented and the estrous cycle was not restored in female rats under experimental conditions of hyperestrogenemia after dopamin precursor injection.

The effect of dopamine agonist parlodel (1 and 5 mg/kg) on the activity of the hypothalamic-pituitary-adrenal system, lactotropic and somatotropic pituitary functions was studied. The content of ACTH and corticosterone in the blood and tissue, aldosterone in the blood, prolactin, somatotropic hormone in the pituitary, catecholamines in the hypothalamus and cerebral cortex demonstrated the inhibitory effect of the drug on the functioning of the hypothalamic-pituitary-adrenal system, and pituitary, lactotropic and somatotropic functions. The mode of parlodel action consists probably in the decrease of turnover rather than in any changes of dopamine and catecholamine content in the hypothalamus and cerebral cortex. Parlodel failed to affect steroid metabolism in the body.

Experiments on rats have shown that the dopamine agonist parlodel produces a noticeable inhibitory effect on function of the pituitary-adrenal system by a decrease in corticotropin secretion and direct influence on aldosterone synthesis and secretion. Changes in corticosterone level caused by parlodel are related to ACTH action and inhibition of activity of the microcirculatory bed of the adrenal fascicular zone. The dopamine agonist parlodel produces no effect on metabolism of the steroid hormones: corticosterone and testosterone in the rat hepatic tissue.

Prolactin (PRL) is synthesized by lactotropic pituitary cells. The corresponding hormonal preparations is dispensed as lactin. Bromocriptine is a dopamine agonist, dopamine being a natural inhibitor of PRL-secretion. PRL receptors in the testis are located on the interstitial cells. PRL effect on the testis depends on the age and species of animals. In the immature animals as well as in the photoperiodic ones PRL stimulates the testis development and the testicular secretion; bromocriptine decreases androgen concentration. In the postpubertal animals PRL is a melatonin antagonist in the dark time but LH synergist at the exposure to light. A high PRL concentration inhibits gonadoliberin formation, LH secretion; testosterone concentration and especially dihydrotestosterone concentration decrease (or do not change) with an elevation of estradiol level that on the whole results in feminization. The cerebral transmitters promoting or inhibiting sexual behavior are involved in the interaction with PRL. Administration of PRL, experimental or pathological hyperprolactinemia are followed by the suppression of ejaculation. Bromocriptine (parlodel) appears to be a pathogenetic therapeutic agent in hyperprolactinemia.