Neuropeptide S: a novel modulator of stress and arousal

Neuropeptide S (NPS) is a recently identified bioactive peptide that modulates stress and arousal. NPS is expressed in a few discrete nuclei in the brainstem, such as the pericoerulear (locus coeruleus (LC)) area and the parabrachial nucleus. NPS activates its cognate G protein-coupled receptor at low nanomolar agonist concentrations and induces elevation of intracellular Ca2+ and cAMP, therefore acting as an excitatory transmitter. The NPS receptor is widely expressed in the brain, including regions known to regulate stress responses such as hypothalamus, thalamus, amygdala and limbic cortex. We have recently reported that the NPS system can modulate stress responses and induce wakefulness based on a battery of behavioral tests. Activation of NPS receptors induces arousal and reduces all sleep stages. At the same time, NPS produces anxiolytic-like effects in rodents. These studies indicate that the NPS system has a unique pharmacological profile to promote both anxiolytic and arousal effects. NPS might interact with other hypothalamic neuropeptide systems that are known to be involved in stress and appetite control and thus might be a valuable target for development of a new class of drugs to treat anxiety disorders.     

Ovarian hormones, aging and stress on hippocampal synaptic plasticity

The ovarian steroid hormones estradiol and progesterone regulate a wide variety of non-reproductive functions in the central nervous system by interacting with molecular and cellular processes. A growing literature from studies using rodent models suggests that 17β-estradiol, the most potent of the biologically relevant estrogens, enhances synaptic transmission and the magnitude of long-term potentiation recorded from in vitro hippocampal slices. In contrast, progesterone has been shown to decrease synaptic transmission and reduce hippocampal long-term potentiation in this model system. Hippocampal long-term depression, another form of synaptic plasticity, occurs more prominently in slices from aged rats. A decrease in long-term potentiation magnitude has been recorded in hippocampal slices from both adult and aged rats behaviorally stressed just prior to hippocampal slice tissue preparation and electrophysiological recording. 17β-estradiol modifies synaptic plasticity in both adult and aged rats, whether behaviorally stressed or not by enhancing long-term potentiation and attenuating long-term depression. The studies discussed in this review provide an understanding of new approaches used to investigate the protective effects of ovarian hormones against aging and stress, and how these hormones impact age and stress-related learning and memory dysfunction.     

The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition

In this review, we report on studies that have assessed the effects of exogenous and endogenous increases in stress hormones on human cognitive performance. We first describe the history of the studies on the effects of using exogenous stress hormones such as glucocorticoids as anti-inflammatory medications on human cognition and mental health. Here, we summarize the cases that led to the diagnosis of glucocorticoid-induced 'steroid psychosis' in human populations and which demonstrated that these stress hormones could thus cross the blood-brain barrier and access the brain where they could influence cognition and mental health. We then summarize studies that assessed the effects of the exogenous administration of glucocorticoids on cognitive performance supported by the hippocampus, the frontal lobes and amygdala. In the second section of the paper, we summarize the effects of the endogenous release of glucocorticoids induced by exposure to a stressful situation on human cognition and we further dissociate the effects of emotion from those of stress on human learning and memory. Finally, in the last section of the paper, we discuss the potential impact that the environmental context to which we expose participants when assessing their memory could have on their reactivity to stress and subsequent cognitive performance. In order to make our point, we discuss the field of memory and aging and we suggest that some of the 'age-related memory impairments' observed in the literature could be partly due to increased stress reactivity in older adults to the environmental context of testing. We also discuss the inverse negative correlations reported between hippocampal volume and memory for young and older adults and suggest that these inverse correlations could be partly due to the effects of contextual stress in young and older adults, as a function of age-related differences in hippocampal volume.     

The effect of "stress hormones" on emotional sensitivity]

Stress is associated with an increased secretion of hormones from the hypothalamus-pituitary-adrenal-axis (HPA-axis). Once released into the blood stream they induce a number of adaptive changes that may also have pertinence to brain functions, resulting, for example in alterations of mood. To provide evidence for a mediation of mood changes by stress related hormone secretion, the influences of a short-term administration of hormones of the HPA-axis on mood and activation were assessed in a total of 182 healthy men (aged between 18 and 34 years in 7 experiments). Effects of intravenously administered hormones on self-perceived mood and activation were assessed by a standardized adjective checklist (Eigenschaftsw?rterliste) in placebo-controlled, double-blind experiments during rest. Results indicated no effects following corticotropin releasing-hormone or cholecystokinin, but specific effects resulted after vasopressin, oxytocin, ACTH-related hormones, and cortisol. Vasopressin and oxytocin increased activation and attenuated arousal and anger, ACTH-related hormones increased sensitivity and diminished extraversion, while cortisol increased activation and concentration. It is concluded that hormones of the HPA-axis specifically affect mood and activation. The pattern of hormonal changes in mood may have adaptive functions by preparing for behavioral and cognitive coping with stress.     

Effects of stress hormones on traumatic memory formation and the development of posttraumatic stress disorder in critically ill patients

A majority of patients after intensive care treatment report traumatic memories from their stay in the intensive care unit (ICU). Traumatic memories can be associated with the development of posttraumatic stress disorder (PTSD) in a subpopulation of these patients. In contrast to other patient populations at risk for PTSD, patients in the ICU often receive exogenously administered stress hormones like epinephrine, norepinephrine, or cortisol for medical reasons and are extensively monitored. ICU patients therefore represent a suitable population for studying the relationship between stress hormones, traumatic memories, and the development of PTSD. Studies in long-term survivors of ICU treatment demonstrated a clear and vivid recall of different categories of traumatic memory such as nightmares, anxiety, respiratory distress, or pain with little or no recall of factual events. The number of categories of traumatic memory recalled increased with the total administered dosages of stress hormones (both catecholamines and cortisol), and the evaluation of these categories at different time points after discharge from the ICU showed better memory consolidation with higher dosages of stress hormones administered. However, the administration of stress doses of cortisol to critically ill patients resulted in more complex findings as it caused a significant reduction in PTSD symptoms measured after recovery. This effect can possibly be explained by a differential influence of cortisol on memory. Increased serum cortisol levels not only result in consolidation of emotional memory but are also known to cause a temporary impairment in memory retrieval which appears to be independent of glucocorticoid effects on memory formation. Disrupting retrieval mechanisms with glucocorticoids during critical illness may therefore act protectively against the development of PTSD by preventing recall of traumatic memories. Our findings indicate that stress hormones influence the development of PTSD through complex and simultaneous interactions on memory formation and retrieval. Our studies also demonstrate that animal models of aversive learning are useful in analyzing and predicting clinical findings in critically ill humans.     

The effects of acute stress and pubertal development on metabolic hormones in the rat

A dramatic change in stress responsiveness occurs during pubertal development such that stress-induced corticosterone secretion in prepubertal animals takes 45-60 min longer to return to baseline compared to adults. Though corticosterone is known to influence energy mobilization, it is presently unknown whether stressors affect other hormones important in energy utilization and metabolism differentially in animals before and after pubertal development. Therefore, we exposed prepubertal (28 days of age) and adult (77 days of age) male rats to a single 30 min session of restraint stress in either the light or dark phase of the animals' light-dark (LD) cycle and measured plasma glucose, insulin and thyroid hormones (thyroxine (T4) and triiodothyronine (T3)). We found similar stress-induced increases in plasma glucose levels in prepubertal and adult animals in the LD phase of the LD cycle. We also found that prepubertal animals have lower circulating insulin and total and free T4 levels, but higher total and free T3 levels compared to adults in both the light and dark phases (LD). Interestingly, insulin and thyroid hormone levels were unaffected by acute stress at either age or time of day. These data indicate that, despite prepubertal animals showing an extended glucocorticoid stress response after a single acute exposure to stress, glucose levels are similarly affected by acute stress in prepubertal and adult animals. Furthermore, though stage of development significantly affects the levels of peripheral metabolic hormones such as insulin, T4 and T3, acute stress does not appreciably influence their secretion before or after puberty.     

Adaptation of anterior pituitary hormones to chronic noise stress in male rats

We have studied the effects of acute and chronic noise on serum levels of pituitary hormones in male Wistar rats. Acute noise increased serum levels of corticosterone, prolactin, and luteinizing hormone and decreased serum GH. FSH was unaffected by this stressor. Chronic noise did not modify basal levels of any hormone studied, however responsiveness of some hormones to the same stimuli was altered. Reduced corticosterone, prolactin, and GH responses to noise was observed after previous chronic exposure to this stimuli. LH response followed the same pattern although it did not reach statistical significance. It might be concluded that adaptation to a repeated stress stimulus is not confined to the pituitary-adrenal axis, however, the degree of adaptation could vary between different hormones.     

The influence of stress hormones on emotional memory: relevance for psychopathology

Substantial progress within recent years has led to a better understanding of the impact of stress on emotional memory. These effects are of relevance for understanding and treating psychopathology. The present selective review describes how emotional memory is modulated through stress hormones. Acute as well as chronic effects are discussed and information from rodent models is compared to human experimental studies and clinical observations. Finally, the relevance of these findings for emotional memory disturbances in psychiatric disorders is exemplified by discussions on neuroendocrine alterations in depression, post traumatic stress disorder and phobias.     

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.     

Libido and hormones

Libido is the drive to have a sexual activity. Gonadal hormones play a major role in activating and maintaining libido in both men and women. Other hormones, though, interact with them in influencing sexuality, such as prolactin and also brain neurotransmitters. The role of hormones declines with age and sexuality becomes more mind-induced. Nevertheless, some aspects of sexuality remain linked to hormones. For example, a reduction of central arousability is typical of hypogonadal state. However, it is not clear at what level of androgen deficiency the loss of libido begins and if adequate external stimuli can overcome a partial deficiency.     

Differential vascular adaptive response to stress exposure in male and female rats: role of gonadal hormones and endothelial cells

Although there are reports concerning a vascular adaptive response to stress in males, this is not yet defined in females. The aim of this study was to delineate functional gender differences in the rat vascular adaptive response to stress and to determine the ability of sex hormones to modulate the stress-induced vascular adaptive response. Responses to noradrenaline were evaluated in aortas, with and without endothelium, from intact, gonadectomized and gonadectomized-hormone-replaced males and females submitted or not to stress (2-h immobilization). Reactivity of the aorta of stressed and non-stressed intact males and females (n = 6-14 per group) was also examined in the presence of L-NAME or indomethacin. Stress decreased and gonadectomy increased maximal responses to noradrenaline in aortas with intact endothelium from both genders. Stress also reduced noradrenaline potency in males. In females, but not males, stress decreased the gonadectomy-induced noradrenaline hyper-reactivity to near that of intact non-stressed rats. Hormone replacement restored the gonadectomy-induced impaired vascular adaptive response to stress. L-NAME, but not indomethacin, abolished the stress-induced decrease in aorta reactivity of males and females. None of the procedures altered reactivity of aortas denuded of endothelium. CONCLUSION: Stress-induced vascular adaptive responses show gender differences. The magnitude of the adaptive response is dependent on testicular hormones and involves endothelial nitric oxide-system hyperactivity.     

Centrifugal acceleration to 3Gz is related to increased release of stress hormones and decreased mood in men and women

It has been suggested that the central and peripheral neural processes (CPNP) are affected by gravitational changes. Based on the previous experiments during parabolic flights, central and peripheral changes may not only be due to the changed gravitational forces but also due to neuroendocrine reactions related to the psycho-physiological consequences of gravitational changes. The present study focuses on the interaction of neuroendocrine changes and the physical and mental states after acceleration to three-time terrestrial gravity (3Gz). Eleven participants (29.4+/-5.1 [SD] years (male (n=8): 30+/-5.1 years; female (n=3): 27.7+/-2.1 years) underwent a 15 min acceleration to 3Gz in a human centrifuge. Before and after the acceleration to 3Gz circulating stress hormone concentrations (cortisol, adrenocorticotropic hormone (ACTH), prolactin, epinephrine, norepinephrine) and perceived physical and mental states were recorded. A second control group of 11 participants underwent the same testing procedure in a laboratory session. Serum cortisol concentration during exposure to the centrifugal acceleration increased by 70%, plasma concentration of ACTH increased threefold, prolactin twofold, epinephrine by 70% and norepinephrine by 45%, whereas the perceived physical well-being decreased. These findings demonstrate that psycho-physiological changes have to be regarded as a relevant factor for the changes in CPNP during phases of hypergravity exposure.     

Sex,genes and hormones

The multidisciplinary symposium convened by the Society for Women's Health Research 'Sex Begins in the Womb' was held at the Crowne Plaza Cabana, Palo Alto, CA, USA, on 1 March 2002.     

Sex hormones in murderers and assaulters

A study of hormonal levels of violent and nonviolent offenders failed to establish any significant differences among murderers, assaulters, and controls. While the results do not suggest a contributory role for random blood hormone levels in facilitating aggressive behavior, further study of complex interactions is necessary to rule out endocrinological factors.     

Neuropeptide and cardiovascular responses to intravenous catheterization in normotensive and hypertensive blacks and whites

Research suggests that heightened cardiovascular and neuroendocrine (typically catecholamine) responses to stressors may lead to the development of hypertension and that there may be race differences in patterns of reactivity that are potentially pathogenic. Certain neuropeptides exert profound effects on blood pressure (BP) and heart rate (HR), yet no published studies have examined relationships between these peptides, hypertensive status, race, and reactivity. Seventeen Black and 20 White normotensive and borderline-hypertensive male 19- to 50-year-olds underwent intravenous catheterization while cardiovascular and neuropeptide responses to the stress of being catheterized were examined. Results indicate that, in response to the stressor, Black hypertensives, showed significantly lower endorphin levels compared to Black normotensives, and White hypertensives showed significantly higher levels of beta-endorphin compared to White normotensives. Groups were not significantly different in endorphin levels at recovery. Black hypertensives also showed significantly higher stressor-induced HR and systolic and diastolic BP compared to White hypertensives and normotensives. Lower levels of beta-endorphin and lower urine sodium excretion were associated with higher BP and HR.     

Steroid hormones and some evolutionary-relevant social interactions

The steroid hormones, testosterone and cortisol, have some common characteristics, but they are related to generally antagonic processes at both the physiological and psychological levels. In addition, they are the product of the activation of two axes, the hypothalamic–pituitary–gonadal (HPG) and hypothalamic–pituitary–adrenal (HPA), which are very sensitive to a wide range of stressors. Our review focuses on the role of testosterone and cortisol in some social situations, such as competition and others related to the challenge hypothesis, that are evolutionary-relevant and have a component of social stress. Research findings are presented on these points, especially emphasizing the relevance of how the individual interprets social stimuli and attributes of the other participant in the interaction, producing consequences in the response pattern to the social situation. This paper presents empirical support for the role of the interaction between the reproductive HPG and stress HPA axes in several social behaviors with important adaptive significance.     

Aggression is suppressed by acute stress but induced by chronic stress: Immobilization effects on aggression, hormones, and cortical 5-HT1B/ striatal dopamine D2 receptor density

Although it has been established by a number of investigators that a variety of stressors are associated with the induction of aggressive behavior, two specific issues remain unanswered. First, it is unclear whether the contexts surrounding stressors (e.g., stressor length and chance of winning over opponents) change outcomes regarding aggressive behavior. Second, if a relationship exists between stress and aggressive behavior, altered levels of stress-related hormone (e.g., corticosterone [CORT]), as well as aggression-related biomarkers (e.g., testosterone [T], density of prefronto-cortical 5-HT(1B) receptor and striatal dopamine D(2) receptor [D2r]) may contribute to changes in aggressive behavior. Thus, we examined how immobilization (with a 1-, 5-, or 10-day exposure) would impact (1) a longitudinal course of aggression toward different-sized opponents, (2) levels of CORT and T, and (3) densities of 5-HT(1B) receptor (5-HT1Br) in the prefrontal cortex (PFC) and D2r in the striatum. It was found that, regardless of small or large opponents, a single 2-h exposure to immobilization reduced aggressive behavior (stress-suppressed aggression) over time, whereas repeated (10-day) exposure to immobilization escalated aggressive behavior (stress-induced aggression). These stress effects persisted up to 1 week of recovery from immobilization stress. Moreover, immobilized rats demonstrated elevated levels of T, but not CORT, as compared with controls. Finally, acute immobilization altered D2r densities in the shell of the nucleus accumbens, and chronic immobilization changed 5-HT1Br in the PFC, including the downregulation of 5-HT1Br densities in the right prelimbic and orbitolateral cortices. The potential relationships among stress, aggression, and 5-HT1Br/D2r roles are discussed.