Role of the serotoninergic system in the acceleration of sexual maturation in wild Norway rats selected for reduced aggressiveness toward humans

The role of the serotoninergic system in acceleration of the sexual development of domesticated rats (Rattus norvegicus) was assessed. The onset of age-related changes in hypothalamic serotonin during prepubertal period occurred earlier in domesticated than in aggressive male rats. Blockade of the serotoninergic system after p-chlorophenylalanine (PCPA) administration on days 40 and 44 delayed the development of the reproductive system in both aggressive and domesticated males. In 60-day-old rats treated with PCPA, levels of testosterone in plasma and the number of mature spermatozoa in epididymis were decreased compared to controls. At the same time, the administration of PCPA on days 30 and 34 did not modify basal testosterone secretion and other parameters in 60-day-old aggressive rats and produced a decrease similar to PCPA injections on days 40 and 44, although less pronounced, in the weights of testes in domesticated animals. Administration of 5-hydroxytryptophan (5-HTP), a precursor of serotonin synthesis, on days 30, 32, 34, 36 and 38 increased plasma testosterone levels and weights of the sex organs in 60-day-old domesticated males, but did not significantly affect the development of reproductive system in aggressive animals. These data indicate that serotonin stimulates sexual development of males during prepubertal period and this activating effect of serotonin occurs earlier in domesticated than in aggressive males. They also suggest that the acceleration in sexual maturation of domesticated rats could result from changes in the ontogenetic dynamic of hypothalamic serotonin induced by a selection for low aggressiveness towards man.     

Role of corticosteroids in the ontogenetic development of behavior in silver foxes

In domesticated at the age from 30-th to 60-th days foxes an intensification of orienting-investigating behaviour takes place in unknown situation. Cortisol level is not changed. In foxes, selected for aggressive behaviour towards man, at 30 days age the orienting-investigating behaviour is also observed, and hormone concentration does not differ from that in domesticated fox-cubs. In aggressive cubs of 45 days a defensive behaviour develops and cortisol content in blood significantly increases. Participation is discussed of adrenal cortex hormones in manifestation of defensive reactions and mechanisms of restriction of sensitive period of socialization.     

Protein synthesis in the critical periods of early postnatal ontogeny: its role in the development of the interspecific aggressive behavior of rats

Chronic administration of cycloheximide to young rats from 15-th to 30-th postnatal day before daily 3-hour seances of their contacts, disturbed the formation of animals intraspecies aggressivity. In adults it was manifested by hyperaggressivity and by changes of proportions of different reactions in the integral act of aggressive behaviour. By their character these disturbances were close to those observed in the young rats completely deprived of social contacts in this period of ontogenesis.     

Effect of selection for behavior on the pituitary-adrenal function of norway ratsRattus norvegicus in postnatal ontogeny

The activity of the pituitary-adrenal system was studied in the Norway rats selected for both maintenance and elimination of the aggressive behavior towards man in the postnatal ontogeny. The selection of the wild rats for domesticated behavior was shown to result in changes of the pituitary-adrenal system formation in the postnatal ontogeny, which is indicated by differences in the dynamics of the adrenals weight as well as of corticosterone content in the blood plasma and in the adrenals both at rest and under stress conditions between the domesticated and aggressive rats.     

Role of the brain neurochemical systems in altering the reactivity of the hypophyseal-adrenal system in the gray rat selected for behavior

Studies have been made of the interrelationship between brain monoaminergic system and pituitary-adrenal function in two groups of the grey rat Rattus norvegicus Berk. One group consisted of non-aggressive rats selected for lack of agonism towards experimentator, the other one included aggressive animals. Domesticated animals exhibited the decreased reaction of the pituitary-adrenocortical complex to emotional stress as well as the decreased response of the endocrine system during stimulation of noradrenaline or serotonin mechanisms of the brain. In addition, noradrenaline and serotonin content of the brain decreased in domesticated rats during emotional stress to a lower extent, as compared to that in aggressive ones. Therefore, one of the sources of correlational changes in the activity of the pituitary-adrenocortical complex during selection for domesticated behaviour is the effect of selection on neurochemical, in particular monoaminergic systems of the brain.     

A mixture of the "antiandrogens" linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion

Prenatal exposure to environmental chemicals that interfere with the androgen signaling pathway can cause permanent adverse effects on reproductive development in male rats. The objectives of this study were to 1) determine whether a documented antiandrogen butyl benzyl phthalate (BBP) and/or linuron (an androgen receptor antagonist) would decrease fetal testosterone (T) production, 2) describe reproductive developmental effects of linuron and BBP in the male, 3) examine the potential cumulative effects of linuron and BBP, and 4) investigate whether treatment-induced changes to neonatal anogenital distance (AGD) and juvenile areola number were predictive of adult reproductive alterations. Pregnant rats were treated with either corn oil, 75 mg/kg/day of linuron, 500 mg/kg/day of BBP, or a combination of 75 mg/kg/day linuron and 500 mg/kg/day BBP from gestational Day 14 to 18. A cohort of fetuses was removed to assess male testicular T and progesterone production, testicular T concentrations, and whole-body T concentrations. Male offspring from the remaining litters were assessed for AGD and number of areolae and then examined for alterations as young adults. Prenatal exposure to either linuron or BBP or BBP + linuron decreased T production and caused alterations to androgen-organized tissues in a dose-additive manner. Furthermore, treatment-related changes to neonatal AGD and infant areolae significantly correlated with adult AGD, nipple retention, reproductive malformations, and reproductive organ and tissue weights. In general, consideration of the dose-response curves for the antiandrogenic effects suggests that these responses were dose additive rather than synergistic responses. Taken together, these data provide additional evidence of cumulative effects of antiandrogen mixtures on male reproductive development.     

Change in tryptophan hydroxylase activity in the brain of silver foxes and wild Norway rats in the course of selection according to behavior

The activity of tryptophan hydroxylase, the key enzyme of serotonin biosynthesis, was determined in the brain of silver foxes and wild rats selected, according to domestic or aggressive behavior, in respect to man. Significant increase of enzyme activity in midbrain of both domesticated rats and domesticated foxes was found, in comparison with that of aggressive animals. It was suggested that genetic mechanisms of the selection according to aggressive behavior, involve the changes of genes responsible for the synthesis of serotonin, the brain neurotransmitter which inhibits this type of behavior.     

The brain catecholamines during domestication of the silver fox Vulpes fulvus

Studies have been made on the content of catecholamines (noradrenaline and dopamine) as well as metabolites of dopamine (3,4-dihydroxyphenylacetic and homovanillic acids) in the brain structures of silver foxes which differ in their handling reactions. The level of noradrenaline was found to be significantly higher in the anterior hypothalamus of domesticated animals; no differences in noradrenaline content were found in the frontal cortex, hippocamp, posterior hypothalamus and midbrain in animals from aggressive and domesticated groups. Dopamine content was higher in the tuberculum olfactorium of domesticated animals, being lower in the striatum and n. accumbens. Metabolite level remained unaffected which is presumably due to changes in dopamine synthesis in the investigated structures. It was concluded that domestication of animals favours the specimens with an altered state of catecholaminergic system of the brain.     

Effect of melatonin on reproductive system in male rat, treated with estrogen in the first day of life.

The study aimed at demonstrating the possible stimulating or inhibitory effect of melatonin on reproductive system of male rats, the function of which was altered by single diethylstilbestrol dose introduced in the first day of life. The single estrogen dose in the first day of life induced in the studied rats, after they reached the adult age, inhibition of spermatogenesis as well as morphological and functional alterations in accessory sexual glands. This was associated with high level of LH gonadotrophin and with lowered testosterone level in the serum. Additional administration of melatonin between 45th and 84th day of life accentuated the above described changes induced by the single estrogen injection. Results of the studies demonstrated that melatonin in the experimental model not only failed to stimulate but provided an additional inhibitory effect on reproductive system in male rat.     

A Comparison of Brain Gene Expression Levels in Domesticated and Wild Animals

Domestication has led to similar changes in morphology and behavior in several animal species, raising the question whether similarities between different domestication events also exist at the molecular level. We used mRNA sequencing to analyze genome-wide gene expression patterns in brain frontal cortex in three pairs of domesticated and wild species (dogs and wolves, pigs and wild boars, and domesticated and wild rabbits). We compared the expression differences with those between domesticated guinea pigs and a distant wild relative (Cavia aperea) as well as between two lines of rats selected for tameness or aggression towards humans. There were few gene expression differences between domesticated and wild dogs, pigs, and rabbits (30–75 genes (less than 1%) of expressed genes were differentially expressed), while guinea pigs and C. aperea differed more strongly. Almost no overlap was found between the genes with differential expression in the different domestication events. In addition, joint analyses of all domesticated and wild samples provided only suggestive evidence for the existence of a small group of genes that changed their expression in a similar fashion in different domesticated species. The most extreme of these shared expression changes include up-regulation in domesticates of SOX6 and PROM1, two modulators of brain development. There was almost no overlap between gene expression in domesticated animals and the tame and aggressive rats. However, two of the genes with the strongest expression differences between the rats (DLL3 and DHDH) were located in a genomic region associated with tameness and aggression, suggesting a role in influencing tameness. In summary, the majority of brain gene expression changes in domesticated animals are specific to the given domestication event, suggesting that the causative variants of behavioral domestication traits may likewise be different.     

Gonadal endocrine function in female silver foxes selected for domesticated behavior

Selection for domesticated behavior in female silver fox is accompanied by a number of changes in endocrine function of ovaries. Significant changes in peripheral blood estradiol and progesterone levels and their production by gonads during anestrous may be an endocrine basis for out-of-season activation of reproductive system and earlier beginning of seasonal reproduction in domesticated females. The increase in the hormone level during preimplantation period of pregnancy and before parturition in tame foxes may influence their productivity.     

Chronic low dose cyclophosphamide treatment of adult male rats: effect on fertility, pregnancy outcome and progeny

Cyclophosphamide is an anticancer and immunosuppressive agent commonly used in men of reproductive age. The relationship between the effects of paternal cyclophosphamide treatment on the male reproductive system and the pregnancy outcome is unknown. To study this relationship, adult male Sprague-Dawley rats were administered saline or cyclophosphamide (1.4, 3.4, and 5.1 mg/kg) daily for 11 wk by gavage. Each male was mated weekly with two females in proestrous; 20 days later, the females were caesarean-sectioned and the number of corpora lutea, resorptions, and normal and abnormal fetuses were noted. After 11 wk of treatment, none of the drug-treated males showed any significant difference compared to controls with respect to male reproductive organ weights, serum testosterone, luteinizing hormone or follicle-stimulating hormone, epididymal sperm counts or fertility. Despite the apparent minimal effects of the treatment regimen on the male reproductive system, there were a number of effects on pregnancy outcome. There was a dose-dependent increase in preimplantation loss at 5-6 wk that was not evident at other times, a progressive dose-dependent increase in postimplantation loss starting at 2 wk, and an increase in malformed and growth-retarded fetuses at 3-4 and 7-9 wk. These results indicate that low dose chronic cyclophosphamide treatment of the male rat can affect the outcome of his progeny; such effects are seen in the absence of any apparent alteration of a number of measures of male reproductive function.     

The effect of the S1A-receptor agonist ipsapirone on behavior types in wild and domesticated rats]

Selective agonist of 1A subtype of serotonine receptors ipsapirone inhibited manifestation of affective kinds of aggression in wild and domesticated rats. Administration of ipsapirone (10 mg/kg) decreased the number of aggressive attacks of wild and domesticated rats in the test of shock-induced aggression and blocked manifestation of defensive reaction to the experimenter in wild rats. Neophobia in wild rats decreased under the influence of ipsapirone. At the same time ipsapirone did not change mouse-killing behaviour either in wild or in domesticated rats. Probably, 5-HT1A receptors the aggressive regulate reaction, which are parts of the complex of defensive behaviour of the wild animals.     

Effect of repeated stress on the function of pituitary-adrenal and immune systems in gray rats selected for behavior

Reaction of pituitary-adrenal axis to a 10-day immobilisation stress and a humoral immune response to subsequent injection of sheep red blood cells were investigated in gray rats selected for enhancement of decrease of aggressive behavior towards humans. It was show that pituitary-adrenal axis reaction of aggressive animals to repeated stress did not change during the experiment, while a decrease of stress-induced corticosterone level was observed already on day 5 of stress. Repeated stress led to enhancement of humoral immune response in aggressive rats, whereas it did not bring about any change in tame animals. based on the obtained data, it could be supposed that breeding of gray rats for domesticated behavior led a faster adaptation to repeated stress and the absence of stimulating influence on humoral immune response in tame rats.     

The role of brain noradrenaline in regulating the endocrine function of the gonads in male brown rats selected for behavior

In two groups of gray rats--nonaggressive ones, selected by the lack of aggression towards investigator, and aggressive animals--studies have been made on the relationship between noradrenaline system of the brain and the activity of pituitary-testicular system. In tame rats, less evident dependence of the gonadal activity on activating effect of noradrenaline was noted. After injection of norepinephrine, dopamine, and serotonin in the same brain region. *****were less significant in tame rats as compared to those in aggressive ones. The disturbed relationship between noradrenaline system of the brain and hypothalamo-pituitary-testicular complex is presumably one of the causes of associate changes in the reproductive system during selection for the domestic type of behaviour.     

Effects of long-term use of fluoxetine on fertility parameters in adult male rats

The effects of long-term ingestion of fluoxetine on fertility were investigated in Sprague-Dawley male rats. Adult male rats were exposed to fluoxetine at a concentration of 200 mg/kg for 60 days. Long-term ingestion of fluoxetine for 60 days caused a great decrease in spermatogenesis in seminiferous tubules of the testes. Sperm motility and density were also significantly reduced in cauda epididymides and testes of the treated group. The weights of reproductive organs (testes, epididymides, ventral prostrate and seminal vesicle) were decreased considerably. The hormonal assay also showed significant decrease in testosterone levels and FSH levels. Testicular cell population dynamics also demonstrated a decrease in the number of both primary and secondary spermatocystes and spermatids in the treatment group. The number of female rats impregnated by male rats on long-term fluoxetine diet had decreased. The number of implantations and the number of viable fetuses were also notably decreased in female rats impregnated by male rats ingested fluoxetine. Fluoxetine caused a slight decrease in body weight, when initial and final body weights were compared in the experimental groups. Levels of ALT and AST were found to be significantly increased in the treated group when compared to the control. Histometery of reproductive organs confirmed these results. In conclusion, these results confirm that the long-term fluoxetine ingestion produce adverse effects on fertility and reproductive system in adult male rat. Thus, it would be of great interest to investigate the impact via long -term treatment with fluoxetine in male human fertility.     

The effect of the domestication of Norway rats and silver foxes on the serotonin S1A- and S2-receptors of the brain]

The specific radioligand binding of serotonin 5-HT1A and 5-HT2 receptors was determined in the frontal cortex and in the hypothalamus of Norway rats and silver foxes. Aggressive wild rats and silver foxes and animals selected for many generations for nonaggressive behavior towards man (domestication) were compared. The binding of the 5-HT1A receptors was found to be significantly higher in domesticated Norway rats and lower in domesticated foxes than in aggressive animals. The specific binding of the 5-HT2 receptors was found to be similar in aggressive and domesticated animals, both in rats and foxes. The data obtained indicate the involvement of 5-HT1A receptors in the hypothalamus into the process of domestication.     

Prenatal Testosterone Exposure Worsen the Reproductive Performance of Male Rat at Adulthood

The reproductive system is extremely susceptible to environmental insults, for example exogenous steroids during gestational development and differentiation. Experimental induction of androgen excess during prenatal life in female animal models reprograms their reproductive physiology, however the fetal programming of the male reproductive system by androgen excess has not been well studied. We aimed to determine the effect of prenatal exposure of two different doses of testosterone on different gestational days, on the male reproductive system using a rat model. Sixteen pregnant rats were randomly divided into two experimental groups and two control groups. Experimental group І were subcutaneously injected with 3 mg free testosterone on gestational days 16-19 and its controls received solvent for that time; experimental group П were subcutaneously injected with 20 mg free testosterone on day 20 of gestational period and its controls received solvent at the same time. The reproductive system morphology and function of 32 male offspring of these study groups were compared at days 6-30-60 of age and after puberty. The anogenital distance of the male offspring of both experimental groups had no significant differences on the different days of measurement, compared with controls. In the offspring of experimental group І, the testes weight, number of Sertoli, Spermatocyte and Spermatid cells, sperm count and motility and the serum concentration of testosterone after puberty were significantly decreased; except for reduction of sperm motility (p< 0.01), the other effects were not observed in the offspring of experimental group ІІ. In summary, our data show that prenatal exposure of male rat fetuses to excess testosterone disrupted reproductive function, an effect highly dependent on the time, duration and level of exposure. It seems that the reproductive system in individuals exposed to high levels of androgens during fetal life should be evaluated at puberty and likely to be treated.     

Effect of selection for behavior on the seasonal characteristics of the reproductive function in brown rats

Artificial selection of grey rats by the domestic type of behaviour resulted in the decrease of the dependence of reproductive function on the effect of photoperiod. Domesticated animals exhibited a significantly lower decrease of the intensity of reproduction in autumn and winter as compared to aggressive ones. One of the causes of this difference is probably the observed shift in the seasonal changes in the level of sex steroids in the blood.