Aggressive behavior in female hamsters: the hormonal basis for fluctuations in female aggressiveness correlated with estrous state

The frequency and sequencing of aggressive behaviors by naive female hamsters change during series of brief encounters, probably because of the lack of stable dominance relations. Such initial encounters seem most representative of interactions likely in free-ranging hamsters and have been emphasized in studies of the hormonal mediation of female aggression. Nonestrous females exhibit intense aggression toward conspecifics of either sex. Estrous females are not aggressive and spend much time in lordosis, indicative of sexual receptivity. The inhibition of fighting on estrous day depends on estrogen and progesterone. Whereas oil-injected adrenalectomized-ovariectomized females fight at high levels, comparable with intact nonestrous females, the combination of 17 beta-estradiol benzoate and progeterone suppresses fighting completely. In contrast, replacement of estradiol, progesterone, or testosterone propionate individually has on consistent effect. Hypophysectomized females also fight at high levels, indicating that pituitary hormones are not required for vigorous aggression. Further, individual anterior pituitary hormones did not produce marked changes in fighting. These results emphasize the roles of estrogen and progesterone in synchronizing aggression with current reproductive state.     

Sexual cycles in female dogs treated with androgen during development

This experiment was conducted to study hormonal and behavioral cycles in female dogs exposed to androgen during development. The four groups, each consisting of five subjects, were "Normal" females, "Prenatal" females exposed to testosterone propionate (TP) before birth, "Postnatal" females injected with TP for 3 months postpartum, and "Prepost" females exposed to TP in utero and again to testosterone for 4--6 weeks after birth. All Normal females had two estrous cycles during which they showed vaginal bleeding, ovulation, progesterone (P) secretion, sexual receptivity, and were attractive to males. All androgen-treated females showed at least 1 cycle with ovulation and P secretion. Three Postnatal females developed the delayed anovulatory syndrome. Genital bleeding through the vagina (Postnatal group), or through the "penis" (Prenatal and Prepost groups), occurred in 4 Postnatal, 3 Prenatal, and 1 Prepost female. Attractiveness for males was observed in all Prenatal and Postnatal females, but in no Prepost subject. Receptivity was present in four of five Prenatal females but not in any Postnatal or Prepost female. Occurrence of cycles in treated females indicated functional integrity and sensitivity to estrogen in brain mechanisms producing gonadotropin-releasing hormones. Absence of receptivity is referred to diminished responsiveness to ovarian hormones in brain mechanisms mediating receptive behavior. Absence of genital bleeding and lack of attractivity are due to lowered response to estrogen in uterine and vaginal epithelium which results in reduced extravasation of blood, and in failure to secrete the putative "pheromonal" agent normally responsible for attractiveness.     

Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.     

Prelordotic behavior in the hamster: a hormonally modulated transition from aggression to sexual receptivity

The behavioral responses of the female golden hamster to a sexually experienced male were analyzed as a function of the stage of the female's estrous cycle. Exogenous estradiol or estradiol followed by progesterone was given to ovariectomized females to determine the role of these hormones in the regulation of cyclic changes in the female's response to the male. Females were paired on a daily basis with sexually active males for 10 min, and behavioral interactions were recorded. Significantly more fighting occurred during early diestrus than later in the cycle. During the 24 hr preceding sexual receptivity, fighting was infrequent. BY 8 HR PRIOR TO THE ONSET OF SEXUAL RECEPTIVITY, 86% OF THE POPULATION EXHIBITED A BEHAVIOR RESEMBLING THE ONSET OF LORDOSIS WITHOUT IMMOBILIZATION (PRELORDOSIS). Following ovariectomy fighting was at a high level (80%--90%). Estradiol replacement, over a 28-day test period, resulted in a significant decrease in aggression and a significant increase in the display of the prelordotic response without inducing lordosis. Initially, the treatment with progesterone following 7 days of estradiol treatment caused the female to display lordosis. After 24 hr a significant increase in aggression, which continued as long as progesterone was present, was observed. After removal of progesterone a significant decrease in aggression occurred. Thus, estradiol causes the female to become tolerant of the male's approach, the female exhibiting prelordosis in response to the male's investigation. Estradiol and progesterone are necessary for normal sexual receptivity; however, after 24 hr, estrogen-progesterone-treated females become agonistic to the male.     

Cardiovascular responses to open-field stress in rats: sex differences and effects of gonadal hormones

We studied sex differences in cardiovascular responses to stress using a new radio-telemetry model in which freely-moving Spontaneously Hypertensive rats (SHR) are exposed to open-field novelty stress. This model allowed simultaneous assessment of cardiovascular and behavioural responses to psychological stress. Female SHR in the diestrous stage of their estrous cycle had markedly greater pressor and tachycardic responses to open-field exposure when compared to either female rats not in diestrous or male SHR. Treatment of ovariectomized SHR with estrogen alone had no significant effect on cardiovascular reactivity, while a combined treatment of estrogen and progesterone slightly, but significantly attenuated their pressor response to open-field stress. In addition, treatment of castrated male rats with testosterone significantly enhanced their pressor responses to stress when compared to values obtained before treatment. None of the hormone treatments had any significant effect on heart rate responses to stress. Neither at different stages of the estrous cycle nor after hormone treatments were there any marked changes in behavioural responses in the open-field, making it unlikely that the differences in cardiovascular stress responses were caused by changes in behavioural activity. These data demonstrate differences in cardiovascular stress responses that seem to be dependent on the stage of the estrous cycle. They suggest that particularly androgens, such as testosterone, may enhance pressor responses to stress. On the other hand, a combination of estrogen and progesterone, rather than estrogen alone, may have a small attenuating effect on cardiovascular reactivity.     

Evidence that a factor besides progesterone, prolactin, or plasma-estradiol-binding protein inhibits estrogen-induced sexual receptivity in pregnant rats.

Daily administration of estradiol benzoate stimulated significantly less lordotic behavior in rats during the second half of pregnancy than in ovariectomized females that received subcutaneous progesterone implants, pituitary grafts that raised plasma prolactin, or both treatments combined. Following an initial facilitation of receptivity, females with progesterone implants showed only moderate reductions in lordosis quotients over 3 test days. The capacity of plasma from pregnant rats to bind estradiol was found to increase significantly during the second half of pregnancy. However, daily administration to pregnant rats of a synthetic estrogen, R 2858, which is not bound by plasma protein, was no more effective than estradiol benzoate in stimulating receptive behavior. Administration of estradiol benzoate also stimulated significantly lower levels of sexual behavior in pregnant females than in females in which pseudopregnancy had been prolonged by previous hysterectomy or induction of uterine decidualization. These findings suggest that some endocrine factor other than progesterone, prolactin, or estradiol-binding protein is primarily responsible for the potent suppression of behavioral responsiveness to estrogen which occurs in pregnant rats. It is suggested that 5 alpha-reduced androgens may cause these behavioral effects.     

Non-ligand activation of estrous behavior in rodents: cross-talk at the progesterone receptor

Estrous behavior in rodents is triggered by the binding of progesterone (P) to its intracellular receptor (PR). Non-steroidal agents (i.e., gonadotropin-releasing hormone, noradrenaline, dopamine and others), acting at the membrane, can facilitate estrous behavior in estrogen-primed rats. This action is mediated through the generation of second messengers (cyclic AMP, cyclic GMP, calcium) which, in turn, phosphorylate through diverse kinase systems (protein kinases A, G or C) either the PR or associated effector proteins linking the PR to the trans-activation machinery. P or its metabolites also activate cyclic AMP-signaling pathways by acting directly on the membrane or by modulating neurotransmitter release. Molecular processes resulting from second messenger signaling pathways and those from the progesterone-RP interaction synergize to elicit a full behavioral response.     

Enhanced feminine sexual behavior and infertility in female rats prenatally treated with an antiestrogen

An attempt to elucidate the possible role of prenatal estrogen on the development of feminine sexual behavior and reproductive function was made by treating females with the antiestrogen CI628 prenatally on days 13-19. Control females were prenatally treated with saline or remained untreated. The animals were delivered by caesarian section on day 22 of pregnancy and placed with foster mothers whose newborn pups had been previously removed. Intact peripubertal females in each treatment group were observed for several reproductive measures, including the capacity to become pregnant. Other females were ovariectomized in adulthood and treated with estradiol benzoate (EB) (1, 1.5, 2 or 4 micro g/rat) and 0.5 mg progesterone and tested for receptivity, proceptivity and sexual partner preference. Two weeks after the completion of these tests, the females were injected daily for 7 days with 0.25 mg testosterone and tested for sexual partner preference and mounting behavior. The results obtained showed accelerated vaginal opening, and infertility in the antiestrogen-treated intact females and enhanced receptivity and proceptivity in response to 1 micro g EB in the antiestrogen ovariectomized females. Sexual partner preference and mounting behavior did not differ between groups. These results suggest an involvement of prenatal estrogen on the development of female reproductive function, but not on behavioral differentiation.     

The role of the noradrenergic system in emotional memory

This contribution is an overview on the role of noradrenaline as neurotransmitter and stress hormone in emotional memory processing. The role of stress hormones in memory formation of healthy subjects can bear significance for the derailment of memory processes, for example, in post traumatic stress disorder (PTSD). Increased noradrenaline levels lead to better memory performance, whereas blocking the noradrenergic receptors with a betablocker attenuates this enhanced memory for emotional information. Noradrenaline appears to interact with cortisol in emotional memory processes, varying from encoding to consolidation and retrieval. Imaging studies show that confronting human subjects with emotional stimuli results in increased amygdala activation and that this activation is noradrenergic dependent. The role of noradrenaline in other brain areas, such as hippocampus and prefrontal cortex, is shortly summarized. Finally, the pros and cons of a therapeutic application of betablockers in the (secondary) prevention of PTSD will be discussed.     

Lactation deficit in OFA hr/hr rats may be caused by differential sensitivity to stress compared with Wistar and Sprague Dawley rats

OFA hr/hr (OFA) rats present a major lactation deficit that impairs offspring survival. To explore whether abnormal stress responsiveness causes this deficit, we compared their hormonal (prolactin, progesterone, and corticosterone) responses to stress (room change and 2-min ether exposure) with those of Wistar and Sprague Dawley (SD) rats. We tested responses during the estrous cycle, pregnancy, lactation, after ovariectomy, and ovarian steroid hormone priming, and responses to suckling. We evaluated hypothalamic expression of receptors for prolactin (PRLRlong) and the isoforms of receptors for progesterone (PRA and B) and estrogen (ERα and β) in late pregnancy. We tested whether administration of an anxiolytic (diazepam) improved lactation. Ether exposure increased circulating levels of the three hormones in the three strains of rats, cycling and ovariectomized, but was less effective in pregnancy and lactation. Elevated estrogen level (estrus and estradiol-treated ovariectomized rats) potentiated the prolactin response more in SD and OFA rats than in Wistar rats. Elevated progesterone level (late pregnancy, lactation, progesterone-treated ovariectomized rats) inhibited the prolactin response less in OFA than in SD or Wistar rats. Ether exposure inhibited the prolactin and oxytocin responses to suckling only in OFA rats. Diazepam treatment increased pup survival rate and the prolactin response to suckling. Hypothalamic total PR mRNA content, assayed by RT-PCR, was higher in pregnant OFA rats compared with SD and Wistar rats, but the PRB/PRA protein ratio determined by Western blot was lowest in Wistar rats, intermediate in OFA rats, and highest in SD rats. The heightened sensitivity to stress of lactating OFA rats may contribute to their lactational deficit and be caused by a combination of hypoprolactinemia and reduced inhibitory capacity of progesterone.     

Central progesterone induces female sexual behavior in estrogen-primed intact males rats

Progesterone induced high levels of female lordotic behavior in 10 of 17 intact, estrogen-primed male rats when it was applied directly to the medial preoptic-anterior hypothalamic area. All 17 males previously had shown lordosis when the serotonergic antagonist methysergide was applied to the same central sites. Few males responded to systemic progesterone and none to intracralial cholesterol. Intradiencephalic Metycaine, a local anesthetic, induced lordosis in eight male that previously had responded to central progesterone. These data indicate that estrogen and progesterone act synergistically to induce lordosis in male rats when progesterone is administered directly to sensitive brain sites.     

Intrasexual interactions among female golden hamsters (Mesocricetus auratus) over the estrous cycle

Social interactions of cycling female golden hamsters paired with ovariectomized animals in large enclosures were primarily agonistic over the 4-day estrous cycle. These aggressive interactions were intense as indicated by frequent occurrences of chase and flight behavior. Dominant and subordinate social ranks were established in the majority of pairs (96%) tested, and even females in sexual heat were capable of attacking and dominating their rivals. Furthermore, cycling females exhibited significantly more aggressive acts than ovariectomized opponents 1 day prior to sexual receptivity. No differences in fighting patterns were found between animals on the other 3 days of the estrous cycle. Additional analyses revealed clear differences in agonistic elements, including flank marking, between dominant and subordinate females regardless of whether they were gonadectomized or intact. These analyses also showed that dominant individuals frequently chased and bit opponents during encounters within their nesting area. The data are examined for implications on the adaptive organization of female hamster agonistic behavior and the neuroendocrine regulation of species-typical behavior over the estrous cycle.     

Gonadal hormones and intrasexual aggressive behavior in female bank voles (Clethrionomys glareolus)

The effects of gonadal hormones on aggressive behavior in the female bank vole was investigated in 10 min home cage tests. Ovariectomized (ovx) or intact females injected with oil, with progesterone (P), with a mixture of progesterone and estrogen (P+E), or with testosterone (T) alone were confronted in a resident-intruder test with unfamiliar, nonoperated females as intruders. Intact females showed aggressive behavior more frequently than ovx females. Ovx females injected with P, with P+E, or with T made significantly more attacks, and these attacks lasted longer than those observed for oil-treated voles. The results indicate that P, the typical female hormone, is responsible for aggressive behavior in female bank voles; however, only T increased the duration of interfemale aggression. Aggr. Behav. 24:63–70, 1998. © 1998 Wiley-Liss, Inc.     

How reward and emotional stimuli induce different reactions across the menstrual cycle

Despite widespread belief that moods are affected by the menstrual cycle, researchers on emotion and reward have not paid much attention to the menstrual cycle until recently. However, recent research has revealed different reactions to emotional stimuli and to rewarding stimuli across the different phases of the menstrual cycle. The current paper reviews the emerging literature on how ovarian hormone fluctuation during the menstrual cycle modulates reactions to emotional stimuli and to reward. Behavioral and neuroimaging studies in humans suggest that estrogen and progesterone have opposing influences. That is, it appears that estrogen enhances reactions to reward, but progesterone counters the facilitative effects of estrogen and decreases reactions to rewards. In contrast, reactions to emotionally arousing stimuli (particularly negative stimuli) appear to be decreased by estrogen but enhanced by progesterone. Potential factors that can modulate the effects of the ovarian hormones (e.g., an inverse quadratic function of hormones' effects; the structural changes of the hippocampus across the menstrual cycle) are also discussed.     

增塑剂DEHP的神经和行为发育毒性

增塑剂邻苯二甲酸二乙基己酯(Di-(2-ethylhexyl) phthalate,DEHP)是一种具有拟雌激素和抗雄激素活性的环境内分泌干扰物,人类和野生动物可通过不同途径终生暴露于DEHP.母体摄入的DEHP可通过胎盘和乳汁转入子代体内并进入脑组织.围生期DEHP暴露性别特异性地改变子代大鼠下丘脑视前区芳香酶活性而影响雌激素合成,并通过改变雌激素受体活性干扰雌激素对脑发育的调节作用.DEHP及其代谢产物可以影响神经细胞的增殖分化和突触形成,干扰性激素调控发育过程中的下丘脑氨基酸递质系统对促性腺激素释放激素分泌的刺激作用,影响中脑多巴胺递质系统发育而诱导自发性多动症.DEHP对脑发育的作用最终影响动物的早期行为、学习记忆和情感等行为发育.     

Monoaminergic mediation of female sexual behavior.

Lordotic behavior was facilitated in estrogen-primed female rats by direct application of progesterone or serotonergic or beta-adrenergic receptor blockers to specific telencephalic, anterior hypothalamic-medial preoptic, or posterior hypothalamic sites. Blockade of the alpha-adrenergic system was ineffective in facilitating lordosis, as was the application of the active drugs to control sites in the thalamus or basal ganglia. Female soliciting behavior was not evoked by any of the treatments. It is concluded that the lordotic behavior component of the female rat's estrous behavior pattern is inhibited by a specific central monoaminergic system that also responds to progesterone. Soliciting behavior appears to be mediated by systems that are anatomically, and possibly neurochemically, separable from those regulating lordosis.     

Role of Glucocorticoids on Rat Brain Metallothionein-I and -III Response to Stress

The metallothionein (MT) gene family consists of four members (MT-I through -IV) that are tightly regulated during development. Whereas MT-I and MT-II are widely expressed isoforms, MT-III has been found to be mainly expressed in the central nervous system in adult animals, and is the only isoform that inhibits survival and neurite formation of cortical neurons in vitro. A number of models of brain injury have been shown to affect MT-III mRNA levels, which has been suggested to be related to the putative neurotrophic role of this protein. However, a stress response will presumably be associated to the brain injury which could, in turn, drive MT-III regulation. In the present report the effect of a classical stress model, immobilization stress, on brain MT regulation has been studied in rats. MT-I+II protein levels were measured by radioimmunoassay in up to eight brain areas and, as expected, it was found that stress increased selectively MT-I+II levels. Adrenalectomy (ADX) had a general decreasing effect on basal MT-I+II levels; however, ADX blunted the MT-I+II response to stress in cerebellum and presumably in frontal cortex and medulla plus pons but not in the hypothalamus. MT-I mRNA measurements were in accordance with the MT-I+II protein levels in the brain areas studied. In contrast to MT-I mRNA, MT-III mRNA levels of brain cortex tended to decrease during stress, although this effect was not statistically significant. ADX also tended to decrease basal MT-III mRNA levels. Northern blot assays of pooled mRNAs suggested similar differential regulation of these two brain MT isoforms in the cerebellum. These results indicate that glucocorticoids mediate brain MT-I+II response to stress in some but not all brain areas, that a role of these hormones is likely also for MT-III, and that the regulation of MT isoforms differs substantially in the brain.     

Evidence for separate control of estrous and circadian periodicity in the golden hamster.

To study the relationship between estrous and circadian periodicity, we investigated the period of the estrous cycle in two types of female golden hamsters: normals (circadian period approximately 24 h) and tau mutants (circadian period approximately 20 h). Records of running wheel activity, general locomotor activity, body temperature, vaginal secretion, and sexual receptivity of hamsters kept under constant lighting conditions indicated an estrous period of approximately 96 h for both groups of animals. The fact that animals with different circadian periods have the same estrous period suggests the existence of separate mechanisms in the control of circadian and estrous periodicity. Circadian periodicity is determined by a pacemaker located in the suprachiasmatic nuclei, whereas estrous periodicity is determined by positive and negative feedback loops involving the hypothalamus, pituitary, and gonads. Coupling of the two mechanisms takes place under at least some conditions, but additional research is necessary to elucidate the mechanisms by which this is accomplished.     

Female lordotic behavior mediated by monoamines in male rats.

Direct application of serotonergic of beta-adrenergic receptor blockers to anterior or posterior areas of the hypothalamus induced lordosis in intact estrogen-primed male rats. Such treatment with an alpha-adrenergic blocker or systemic administration of progesterone failed to increase lordosis. Centrally elicited lordosis did not occur without estrogen priming. Anatomical and neurochemical similarity may exist in the brain mechanism mediating lordotic behavior in male and female adult rats.     

Stress and emotional memory: a matter of timing

Stressful events activate the amygdala and a network of associated brain regions. Studies in both humans and rodents indicate that noradrenaline has a prominent role in this activation. Noradrenaline induces a hypervigilant state that helps to remember the event. This mnemonic effect is enhanced when the situation is so stressful that substantial amounts of corticosteroids are released and reach the amygdala. The combination of the two hormones leads to optimal strengthening of contacts and thus memory. Yet, rises in corticosteroid levels that are not precisely synchronized with noradrenaline release do not act synergistically but rather prevent or suppress the effect of noradrenaline. This dynamic interaction illustrates the adaptive and potentially protective capacity of corticosteroids regarding traumatic memories.