Prenatal ethanol exposure alters the effects of gonadectomy on hypothalamic-pituitary-adrenal activity in male rats

Prenatal ethanol exposure has marked effects on development of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. In adulthood, ethanol-treated rats show altered gonadal hormone responses and reproductive function, and increased HPA responsiveness to stressors. Importantly, prenatal ethanol differentially alters stress responsiveness in adult males and females, raising the possibility that the gonadal hormones play a role in mediating prenatal ethanol effects on HPA function. To examine a possible testicular influence on HPA activity in males, we compared the effects of gonadectomy on HPA stress responses of adult male offspring from ethanol, pair-fed (PF) and ad libitum-fed control dams. Intact ethanol-treated rats showed increased adrenocorticotrophic hormone (ACTH) but blunted testosterone and luteinising hormone (LH) responses to restraint stress, and no stress-induced elevation in arginine vasopressin (AVP) mRNA levels compared to those observed in PF and/or control rats. Gonadectomy: (i) significantly increased ACTH responses to stress in control but not ethanol-treated and PF males; (ii) eliminated differences among groups in plasma ACTH and AVP mRNA levels; and (iii) altered LH and gonadotrophin-releasing hormone responses in ethanol-treated males. Taken together, these findings suggest that central regulation of both the HPA and HPG axes are altered by prenatal ethanol exposure, with normal testicular influences on HPA function markedly reduced in ethanol-treated animals. A decreased sensitivity to inhibitory effects of androgens could contribute to the HPA hyperresponsiveness typically observed in ethanol-treated males.     

Differential responses toward conditioned and unconditioned stimuli,but decreased hypothalamic-pituitary-adrenal axis responsiveness in neonatal hippocampal lesioned monkeys

The hippocampus is important for long-term memory storage, but also plays a role in regulating the hypothalamic-pituitary-adrenal (HPA) axis and emotional behaviors. We previously reported that early hippocampal damage in monkeys result in increased anxious expression and blunted HPA responses to an acute stressor. Here, we further probe their responses toward aversive stimuli (conditioned and unconditioned) and evaluate HPA axis dysfunction. Responses toward social, innate, and learned aversive stimuli, fear potentiated acoustic startle, and pituitary-adrenal function were investigated in 13 adult rhesus monkeys with neonatal hippocampal lesions (Neo-Hibo=6) and controls (Neo-C=7). Neo-Hibo monkeys’ responses depend on the type of unconditioned stimulus, with increased anxiety behaviors toward social and learned, but decreased reactivity toward innate stimuli. Neo-C and Neo-Hibo monkeys exhibited similar performance learning conditioned cues and safety signals. Neo-Hibo monkeys were less sensitive to HPA axis stimulation, potentially suggesting adrenal fatigue. Current findings suggest that the hippocampus plays a large role in regulating not only anxiety behaviors, but also the HPA-axis, a neural system crucial to regulate how we respond to the world around us. These data have important clinical significance considering that many developmental neuropsychiatric disorders exhibit altered hippocampal structure and function, emotional and HPA axis dysregulation.     

The hidden dimensions of the competition effect: Basal cortisol and basal testosterone jointly predict changes in salivary testosterone after social victory in men

Dominance struggles appear to affect hormone concentrations in many mammalian species, such that higher concentrations of testosterone are seen in winners of competitions, compared to losers. This so-called, "competition effect" has received inconsistent empirical support, suggesting that additional psychological (e.g., mood), situational (i.e., nature of the competition) and physiological (e.g., cortisol) variables might intervene in modulating testosterone fluctuations after social contests. We investigated possible interactions between the hypothalamic-pituitary-gonadal (HPG) axis and the hypothalamic-pituitary-adrenal (HPA) stress axis in predicting transient changes in testosterone after social victory or defeat on a familiar competitive task. In particular, the present study examined the dual-hormone hypothesis - proposing that baseline cortisol potently modulates the competition effect (Mehta and Josephs, 2010) - in a sample of healthy young men engaged in head-to-head competition on a widely played commercial videogame, Tetris. We found a significant interaction between HPG and HPA axes status and the competition effect on testosterone in the randomly assigned videogame winners, such that winners with a pre-competition combination of high baseline testosterone and low baseline cortisol exhibited significantly greater post-competition testosterone concentrations. The randomly assigned videogame losers showed significantly decreased post-competition levels of testosterone. Possible biological and evolutionary mechanisms underlying this phenomenon are discussed.     

Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat

The present study investigated the effects of post-weaning social isolation (SI) on behavioural and neuroendocrine reactivity to stress of male and female rats. Innate aspects of fear and anxiety were assessed in the open field and elevated plus maze tests. Spontaneous startle reflex and conditioned fear response were further investigated. The neuroendocrine response of isolates was examined by measuring basal and stress release of ACTH and corticosterone and by evaluating the mRNA expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors using in situ hybridization. Locomotor activity in the open field was not modified by chronic SI. In males, but not females, SI produced an anxiogenic profile in the elevated plus maze. Male isolates showed a trend towards increased startle reflex amplitude relative to socially-reared controls. Moreover, SI in males produced alterations of the HPA axis functioning as reflected by higher basal levels of ACTH, and enhanced release of ACTH and corticosterone following stress. In contrast, startle response or HPA axis functioning were not altered in female isolates. Social isolates from both genders showed reduced contextual fear-conditioning. Finally, the mRNA expression of MR and GR was not modified by SI. The results of the present study suggest that chronic SI increases emotional reactivity to stress and produces a hyperfunction of the HPA axis in adult rats, particularly in males.     

Gonadal hormones modulate the HPA‐axis and the SNS in response to psychosocial stress

Exposure to stress activates both the hypothalamus‐pituitary‐adrenal (HPA) axis and the sympathetic nervous system (SNS). A growing body of research points to the contribution of sex hormones (testosterone, estrogen, and progesterone), the end products of the hypothalamus‐pituitary‐gonadal (HPG) axis, in modulating stress reactivity. The present study aimed at investigating the potential modulating role of sex hormones on HPA and SNS reactivity to psychosocial stress. The reactivity, induced by the Trier Social Stress Test, was analyzed by measuring the levels of cortisol and alpha‐amylase (markers for SNS activity) in four saliva samples each of 21 men and 37 women (17 not using oral contraceptives and in their luteal phase, and 20 women using oral contraceptives). In addition, basal sex hormones were sampled prior to the psychosocial stress exposure. Results revealed that controlling for testosterone, estrogen, and progesterone diminished the impact of stress on cortisol reactivity and on alpha‐amylase reactivity. Moreover, controlling for sex hormones also diminished the differential pattern of cortisol reactivity in each experimental group among responders. Furthermore, correlation analyses revealed differences between groups in the association between sex hormones and alpha‐amylase. The present findings indicate a modulatory role for sex hormones in HPA and SNS reactivity and emphasize the need for control of sex hormone fluctuations when examining cortisol and alpha‐amylase reactivity to stress.     

Hydrocortisone suppression of the fear-potentiated startle response and posttraumatic stress disorder

This study examined the effects of oral administration of 20mg hydrocortisone on baseline and fear-potentiated startle in 63 male veterans with or without PTSD. The procedure was based on a two-session, within-subject design in which acoustic startle eyeblink responses were recorded during intervals of threat or no threat of electric shock. Results showed that the magnitude of the difference between startle responses recorded during anticipation of imminent shock compared to "safe" periods was reduced after hydrocortisone administration relative to placebo. This effect did not vary as a function of PTSD group nor were there were any significant group differences in other indices startle amplitude. Findings suggest that the acute elevations in systemic cortisol produced by hydrocortisone administration may have fear-inhibiting effects. This finding may have implications for understanding the role of hypothalamic-pituitary-adrenal (HPA)-axis function in vulnerability and resilience to traumatic stress.     

Inhibitory Function of the Dorsomedial Hypothalamic Nucleus on the Hypothalamic–Pituitary–Adrenal Axis Response to an Emotional Stressor but not Immune Challenge

Accumulating evidence implicates the dorsomedial hypothalamic nucleus (DMH) in the regulation of autonomic and neuroendocrine stress responses. However, although projections from the DMH to the paraventricular hypothalamic nucleus (PVN), which is the critical site of the neuroendocrine stress axis, have been described, the impact of DMH neurones in the modulation of hypothalamic‐pituitary‐adrenal (HPA) axis activation during stress is not fully understood. The present study aimed to investigate the role of the DMH in HPA axis responses to different types of stimuli. Male Sprague–Dawley rats fitted with a chronic jugular venous catheter were exposed to either an emotional stressor (elevated platform‐exposure) or immune challenge (systemic interleukin‐1β administration). Bilateral electrolytic lesions of the DMH disinhibited HPA axis responses to the emotional stressor, as indicated by higher plasma adrenocorticotrophic hormone levels during and after elevated platform exposure in lesioned animals compared to sham‐lesioned controls. Moreover, DMH‐lesioned animals showed increased neuronal activation in the PVN, as indicated by a higher c‐Fos expression after elevated‐platform exposure compared to controls. By contrast, DMH‐lesions had no effects on HPA axis responses to immune challenge. Taken together, our data suggest an inhibitory role of DMH neurones on stress‐induced HPA axis activation that is dependent upon the nature of the stimulus being important in response to an emotional stressor but not to immune challenge.     

Dissociation of the morphological correlates of stress-induced anxiety and fear

Chronic stress is a powerful modulator of emotional behaviour. Previous studies have shown that distinct neuronal pathways modulate different emotional behaviours: while the amygdala plays a key role in fear-conditioned-to-cue stimuli, the bed nucleus of stria terminalis (BNST) is implicated in anxiety behaviour and responses to contextual stimuli. In addition, the BNST is directly involved in the regulation of the hypothalamus–pituitary–adrenal (HPA) axis. In the present study, we assessed anxiety (measured in the elevated-plus maze and acoustic startle apparatus) and fear-conditioned responses to light stimuli in rats that had been exposed to either chronic unpredictable stress or corticosterone for 28 days; thereafter, stereological estimates of the BNST and amygdaloid complex were performed, followed by three-dimensional morphometric dendritic analysis. Results show that chronic stress induces hyperanxiety without influencing fear conditioning or locomotion and exploratory activity. Stress-induced hyperanxiety was correlated with increased volumes of the BNST but not of the amygdala. Dendritic remodelling was found to make a significant contribution to the stress-induced increase in BNST volume, primarily due to changes in the anteromedial area of the BNST, an area strongly implicated in emotional behaviour and in the neuroendocrine control of the stress response. Importantly, all of the effects of stress were recapitulated by exogenous corticosterone. In conclusion, this study shows that chronic stress impacts on BNST structure and function; its findings pertain to the modulation of emotional behaviour and the maladaptive response to stress.     

Prenatal Social Stress in the Rat Programmes Neuroendocrine and Behavioural Responses to Stress in the Adult Offspring: Sex‐Specific Effects

Stress exposure during pregnancy can ‘programme’ adult behaviour and hypothalamic‐pituitary‐adrenal (HPA) axis stress responsiveness. In the present study, we utilised an ethologically relevant social stressor to model the type of stress that pregnant women may experience. We investigated the effects of social defeat by a resident lactating rat over 5 days during the last week of pregnancy on the pregnant intruder rat HPA axis, and on HPA responsivity to stress and anxiety‐related behaviour in the adult offspring of the socially‐defeated intruder rats. HPA axis responses after social defeat were attenuated in the pregnant rats compared to virgin females. In the adult offspring, systemic interleukin (IL)‐1β or restraint increased adrenocorticotrophic hormone and corticosterone secretion in male and female control rats; however, in prenatally stressed (PNS) offspring, HPA responses were greatly enhanced and peak hormone responses to IL‐1β were greater in females versus males. Male PNS rats displayed increased anxiety behaviour on the elevated plus maze; however, despite marked changes in anxiety behaviour across the oestrous cycle, there were no differences between female control and PNS rats. Investigation of possible mechanisms showed mineralocorticoid mRNA levels were reduced in the hippocampus of male and female PNS offspring, whereas glucocorticoid receptor mRNA expression was modestly reduced in the CA2 hippocampal subfield in female PNS rats only. Corticotropin‐releasing hormone mRNA and glucocorticoid receptor mRNA expression in the central amygdala was greater in PNS males and females compared to controls. The data obtained in the present study indicate that prenatal social stress differentially programmes anxiety behaviour and HPA axis responses to stress in male and female offspring. Attenuated glucocorticoid feedback mechanisms in the limbic system may underlie HPA axis hyper‐reactivity to stress in PNS offspring.     

Adrenal axis activation by chronic social stress fails to inhibit gonadal function in male rats

Stress in males via the hypothalamic-pituitary-adrenal (HPA) axis may set into motion varied physiological alterations, including dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. However, the influence of the HPA on the HPG axis may not always be inhibitory. Presence or absence of stimuli of sexual significance that typically activates the HPG axis may alter the influence of the adrenal axis on gonadal axes. In this project, we used male rats and chronic social stimulation that included brief or extended periods with female rats to examine HPA-HPG axes interactions. In experiment 1, we used intact males and a ‘chronic social stress’ paradigm developed in our previous research that induces social instability by daily changing the membership of group-housed males with females. Thymus weight was reduced and corticosterone levels were marginally increased by chronic social stress, indicating a HPA axis hyperactivity. The HPG axis was also activated as shown by the increased weight of the androgen-sensitive sex structures. These results indicate that when these two axes are stimulated together, neither interferes with nor suppresses activities of the other. Implants of corticosterone pellets to adrenalectomized animals that maintained constant, high corticosterone levels failed to reverse the gonadal hyperactivity induced by sexual stimulation. In a second experiment, we studied the influence of different intensity of sexual stimulations on HPA-HPG axes interactions. Increased corticosterone levels and adrenal weight, indicating a HPA hyperactivity, failed to inhibit HPG hyperactivity as measured by the increased sexual organs weight, whatever the sexual intensity of the stimulation. This work demonstrates that the gonadal axis is freed from suppression when sexual stimulation occurs together with stress. The general conclusion is that the nature of complex social settings is important in determining interactions between the two neuroendocrine axes.     

Encoding and decoding mechanisms of pulsatile hormone secretion

Ultradian pulsatile hormone secretion underlies the activity of most neuroendocrine systems, including the hypothalamic‐pituitary adrenal (HPA) and gonadal (HPG) axes, and this pulsatile mode of signalling permits the encoding of information through both amplitude and frequency modulation. In the HPA axis, glucocorticoid pulse amplitude increases in anticipation of waking, and, in the HPG axis, changing gonadotrophin‐releasing hormone pulse frequency is the primary means by which the body alters its reproductive status during development (i.e. puberty). The prevalence of hormone pulsatility raises two crucial questions: how are ultradian pulses encoded (or generated) by these systems, and how are these pulses decoded (or interpreted) at their target sites? We have looked at mechanisms within the HPA axis responsible for encoding the pulsatile mode of glucocorticoid signalling that we observe in vivo. We review evidence regarding the ‘hypothalamic pulse generator’ hypothesis, and describe an alternative model for pulse generation, which involves steroid feedback‐dependent endogenous rhythmic activity throughout the HPA axis. We consider the decoding of hormone pulsatility by taking the HPG axis as a model system and focussing on molecular mechanisms of frequency decoding by pituitary gonadotrophs.     

Plasma testosterone levels in patients with combat-related posttraumatic stress disorder

BACKGROUND: An abnormal level of androgens has been reported in various psychiatric disorders and the important role of androgens in the regulation of human sexuality, aggression, cognition, emotions and personality have been described. Previous studies in the area of stress and the hypothalamic-pituitary-gonadal (HPG) system in humans indicate that circulating testosterone levels are suppressed by physical and psychological stress. However, there is also evidence that plasma levels of testosterone can increase during potentially stressful events and may be elevated in combat-related posttraumatic stress disorder (CR-PTSD) in comparison with normal subjects and major depressive disorder patients. METHODS: The aim of the present study was to examine the possible involvement of the HPG system in chronic untreated CR-PTSD. To this end, we assessed the morning plasma levels of testosterone and cortisol in never-treated chronic CR-PTSD outpatients compared with normal healthy controls. RESULTS: There were no statistically significant differences between the CR-PTSD patients and healthy control subjects in morning plasma testosterone (547.8 +/- 152.2 ng/dl vs. 565.6 +/- 122.4 ng/dl; p = 0.7) and cortisol (19.0 +/- 8.5 microg/dl vs. 15.4 +/- 5.1 microg/dl; p = 0.1) levels. However, a significant correlation between plasma testosterone level and avoidance symptom scores of the Impact of Events Scale (IES) was found in the CR-PTSD patients (r = 0.43, p < 0.05). CONCLUSIONS: The findings of plasma testosterone levels comparable with normal controls in CR-PTSD patients may indicate that the previously described reduction in testosterone levels in normal subjects under stressful conditions may reflect the acute stress response of the HPG axis, in contrast to an adaptation of the HPG axis under chronic psychological stress.     

Gonadal steroid hormones and the hypothalamo–pituitary–adrenal axis

The hypothalamo–pituitary–adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, prior to generating an appropriate response is the animal’s reproductive status. Thus, PVN neurons express androgen and estrogen receptors and receive input from sites that also express these receptors. Consequently, changes in reproduction and gonadal steroid levels modulate the stress response and this underlies sex differences in HPA axis function. This review examines the make up of the HPA axis and hypothalamo–pituitary–gonadal (HPG) axis and the interactions between the two that should be considered when exploring normal and pathological responses to environmental stressors.     

Alterations in diurnal cortisol rhythm and acoustic startle response in nonhuman primates with adverse rearing.

BACKGROUND: Early adverse experiences represent risk factors for the development of anxiety and mood disorders. Studies in nonhuman primates have largely focused on the impact of protracted maternal and social deprivation, but such intense manipulations also result in severe social and emotional deficits very difficult to remediate. This study attempts to model more subtle developmental perturbations that may increase the vulnerability for anxiety/mood disorders but lack the severe deficits associated with motherless rearing. METHODS: We investigated the consequences of repeated maternal separations between 3 to 6 months of age on rhesus monkeys' hypothalamic-pituitary-adrenal (HPA) axis function and acoustic startle reactivity. RESULTS: Repetitive maternal separation led to increased cortisol reactivity to the separation protocol in female infants and alterations in mother-infant interaction. It also resulted in a flattened diurnal rhythm of cortisol secretion and increased acoustic startle reactivity at later ages. CONCLUSIONS: Macaques with adverse rearing exhibited short-term and long-term alterations in HPA axis function and increased acoustic startle response comparable with changes associated with mood/anxiety disorders. The magnitude of HPA axis reactivity to the separations and the alterations in mother-infant relationship detected during the separation protocol predicted some of the alterations in HPA axis and emotionality exhibited later in life.     

A Role for the Androgen Metabolite, 5α-Androstane-3β,17β-Diol, in Modulating Oestrogen Receptor β-Mediated Regulation of Hormonal Stress Reactivity

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurones in the paraventricular nucleus of the hypothalamus (PVN) that synthesise and secrete corticotrophin-releasing hormone (CRH). Other PVN neuropeptides, such as arginine vasopressin and oxytocin, can also modulate activity of CRH neurones in the PVN and enhance CRH secretagogue activity of the anterior pituitary gland. In rodents, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis after stress than do males. These sex differences primarily result from opposing actions of sex steroids, testosterone and oestrogen, on HPA function. Ostreogen enhances stress activated adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) secretion, whereas testosterone decreases the gain of the HPA axis and inhibits ACTH and CORT responses to stress. Data show that androgens can act directly on PVN neurones in the male rat through a novel pathway involving oestrogen receptor (ER)β, whereas oestrogen acts predominantly through ERα. Thus, we examined the hypothesis that, in males, testosterone suppresses HPA function via an androgen metabolite that binds ERβ. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalisation of ERβ in oxytocin-containing cells of the PVN. Hence, in this review, we address the possibility that testosterone inhibits HPA reactivity by metabolising to 5α-androstane-3β,17β-diol, a compound that binds ERβ and regulates oxytocin containing neurones of the PVN. These findings suggest a re-evaluation of studies examining pathways for androgen receptor signalling.     

Sensitivity to glucocorticoid-mediated fast-feedback regulation of the hypothalamic-pituitary-adrenal axis is dependent upon stressor specific neurocircuitry

Fos-protein immunoreactivity (Fos-IR) was used to identify neurocircuits potentially participating in the regulation of hypothalamic–pituitary–adrenal (HPA) axis sensitivity to glucocorticoid-mediated fast-feedback in rats exposed to the physical stressor, hemorrhage, or the psychological stressor, airpuff startle. Marked regional brain differences in the Fos-IR expression were observed in response to these stressors. Specifically, after hemorrhage, nuclear Fos-IR increased in the nucleus of the solitary tract and other brainstem regions known to regulate hemodynamic processes including the supraoptic nucleus, and the magnocellular division of hypothalamic paraventricular nucleus (PVN). In contrast, after airpuff startle Fos-IR increased in the dorsomedial and lateral hypothalamus as well as in the lateral septum. Thus, activation of brainstem neurocircuits predominated after hemorrhage whereas activation of forebrain neurocircuits predominated after airpuff startle. In other regions, the magnitude of stressor-induced Fos-IR expression varied in a region-specific manner. When stressor exposure was preceded by administration of corticosterone to achieve levels within the physiological range after stressors, HPA axis responses were suppressed in response to the airpuff startle but not to either a small or moderate hemorrhage. In conclusion: (1) fast-feedback mediated inhibition of HPA axis activity is critically dependent upon stressor modality; (2) this apparent selectivity is reflected by differences in the nature of the neurocircuitry mediating these stressors. It is suggested that determination of the central actions of glucocorticoids in mediating fast-feedback regulation of the HPA axis requires evaluation of the interactions between activated glucocorticoid receptors and intracellular signaling cascades evoked by convergent neuronal input.     

Influence of 6-OHDA lesion of central noradrenergic systems on corticosteroid receptors and neuroendocrine responses to stress

Two types of receptor for adrenocortical hormones (type I or mineralocorticoid and type II or glucocorticoid) in the hippocampus and hypothalamus mediate the effects of corticosteroids on various brain functions including the negative feedback control of hypothalamo-pituitary-adrenal (HPA) axis activity. These brain regions are also densely innervated by noradrenergic terminals which may play a role in the regulation of HPA axis activity and the feedback action of corticosteroids. However, direct evidence for a noradrenergic control of corticosterone receptors is lacking. The present experiments tested the effects of 6-hydroxydopamine lesion of noradrenergic ascending pathways at the level of the pedunculus cerebellaris superior (PCS) on the status of type I and type II corticosteroid receptors. Binding of [3H]corticosterone was evaluated in cytosolic fractions of 24-h adrenalectomized animals 3 weeks after surgery. The PCS lesion produced an up-regulation of type I corticosteroid receptors in the hippocampus and of the type II receptor in the hypothalamus. The number of these receptors (Bmax) increased without any change in their affinity for corticosterone (Kd). Furthermore, in a functional study, we tested the effects of the lesion on the neuroendocrine responses to stress. Plasma corticosterone levels were lower in lesioned rats both under basal conditions and in response to the stress of gentle handling or exposure to footshock, indicating reduced activity of the HPA axis. These results are in line with recent studies indicating a facilitatory function of noradrenergic pathways on the HPA axis and suggest that this action could be mediated via a modulation of corticosteroid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic psychosocial stress affects corticotropin-releasing factor in the paraventricular nucleus and central extended amygdala as well as urocortin 1 in the non-preganglionic Edinger-Westphal nucleus of the tree shrew

Stressful stimuli evoke neuronal and neuroendocrine responses helping an organism to adapt to changed environmental conditions. Chronic stressors may induce maladaptive responses leading to psychiatric diseases, such as anxiety and major depression. A suitable animal model to unravel mechanisms involved in the control of adaptation to chronic stress is the psychological subordination stress in the male tree shrew. Subordinate male tree shrews exhibit chronic hypothalamo-pituitary-adrenal (HPA) activation as reflected in continuously elevated cortisol secretion, and structural changes in the hippocampal formation. Corticotropin-releasing factor (CRF) is the major peptide released upon activation of the HPA axis in response to stress. Recent evidence suggests that besides CRF, urocortin 1 (Ucn1) also plays a role in stress adaptation. We have tested the significance of CRF and Ucn1 in adaptation to chronic psychosocial stress in male tree shrews exposed for 35 days to daily psychosocial conflict, by performing semi-quantitative immunocytochemistry for CRF in the parvocellular hypothalamic paraventricular nucleus (pPVN), extended amygdala, viz. central extended amygdala (CeA) and dorsolateral nucleus of the bed nucleus of the stria terminalis (BNSTdl) as well as that for Ucn1 in the non-preganglionic Edinger-Westphal nucleus (npEW). Compared to unstressed animals, psychosocial stress resulted in an immediate and sustained activation of the HPA axis and sympathetic tone as well as reduced testosterone concentration and decreased body and testis weights vs. non-stressed tree shrews. In the pPVN, the number of CRF-immunoreactive neurons and the specific signal density of CRF-immunoreactive fiber terminals in the CeA were strongly reduced (-300 and -40%, respectively; P<0.05), whereas no significant difference in CRF fiber density was found in BNSTdl. The npEW revealed 4 times less Ucn1-immunoreactive neurons (P<0.05). These clear effects on both Ucn1- and CRF-neuropeptide contents may reflect a crucial mechanism enabling the animal to adapt successfully to the stressors, and point to the significance of the pPVN, CeA and npEW in stress-induced brain diseases.     

Modulation of the hypothalamo-pituitary-adrenocortical axis by caffeine

Although caffeine is the most consumed psychoactive substance in the world, the extents of many of its effects are unknown. High doses of caffeine have been shown to activate the HPA axis while the effects of low to moderate doses have usually not been described in detail. Moreover, although several lines of evidence suggest that low doses of caffeine may restrain some negative affective states, the possible modulatory role of caffeine on HPA axis activation induced by a stressful stimulus has not been described. Thus, the present studies investigated the possible modulatory effects of low to moderate doses of caffeine on moderate to high HPA axis activation induced by different intensities of loud noise. First, in order to test this modulation, time courses for adrenocorticotropic hormone (ACTH) and corticosterone responses to loud noise stress and to caffeine were defined, in rats. Plasma ACTH and corticosterone levels peaked 30 min from the onset of noise presentation, and rapidly declined after noise termination. A low caffeine dose of 2 mg/kg significantly increased plasma corticosterone and ACTH levels 30 min following injections, but levels returned to baseline 60 min following injections. Caffeine doses of 30 mg/kg and higher elevated plasma hormone levels for at least 2h. Doses of 2 or 10mg/kg, however, did not modulate endocrine responses to loud noise presentation. It is concluded that although caffeine activates the HPA axis, low to moderate doses do not modulate HPA axis responses to stressful stimuli.     

Adaptive responses of the maternal hypothalamic-pituitary-adrenal axis during pregnancy and lactation

Over the past 40 years, it has been recognised that the maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes adaptations through pregnancy and lactation that might contribute to avoidance of adverse effects of stress on the mother and offspring. The extent of the global adaptations in the HPA axis has been revealed and the underlying mechanisms investigated within the last 20 years. Both basal, including the circadian rhythm, and stress-induced adrenocorticotrophic hormone and glucocorticoid secretory patterns are altered. Throughout most of pregnancy, and in lactation, these changes predominantly reflect reduced drive by the corticotropin-releasing factor (CRF) neurones in the parvocellular paraventricular nucleus (pPVN). An accompanying profound attenuation of HPA axis responses to a wide variety of psychological and physical stressors emerges after mid-pregnancy and persists until the end of lactation. Central to this suppression of stress responsiveness is reduced activation of the pPVN CRF neurones. This is consequent on the reduced effectiveness of the stimulation of brainstem afferents to these CRF neurones (for physical stressors) and of altered processing by limbic structures (for emotional stressors). The mechanism of reduced CRF neurone responses to physical stressors in pregnancy is the suppression of noradrenaline release in the PVN by an up-regulated endogenous opioid mechanism, which is induced by neuroactive steroid produced from progesterone. By contrast, in lactation suckling the young provides a neural stimulus that dampens the HPA axis circadian rhythm and reduces stress responses. Reduced noradrenergic input activity is involved in reduced stress responses in lactation, although central prolactin action also appears important. Such adaptations limit the adverse effects of excess glucocorticoid exposure on the foetus(es) and facilitate appropriate metabolic and immune responses.