Rat and mouse strains differ in behavioral and physiological characteristics, and such differences can contribute to explain discrepant results between laboratories and better select the most appropriate strain for a particular purpose. Differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis are particularly important given the pivotal role of this system in determining consequences of exposure to stressors. In this regard, Long-Evans (LE) rats are widely used in stress research, but there is no specific study aiming at thoroughly characterizing HPA activity in LE versus other extensively used strains. In a first experiment, LE showed higher resting ACTH and corticosterone levels only at certain points of the circadian rhythm, but much greater ACTH responsiveness to stressors (novel environment and forced swim) than Sprague-Dawley (SD) rats. Accordingly, enhanced corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus of the hypothalamus and reduced expression of glucocorticoid receptors were observed in the hippocampal formation. Additionally, they are hyperactive in novel environments, and prone to adopt passive-like behavior when compared to SD rats. Supporting that altered HPA function has a marked physiological impact, we observed in another set of animals much lower thymus weight in LE than SD rats. Finally, to demonstrate that LE rats are likely to have higher HPA responsiveness to stressors than most strains, we studied resting and stress levels of HPA hormones in LE versus Wistar and Fischer rats, the latter considered an example of high HPA responsiveness. Again, LE showed higher resting and stress levels of ACTH than both Wistar and Fischer rats. As ACTH responsiveness to stressors in LE rats is stronger than that previously reported when comparing other rat strains and they are commercially available, they could be an appropriate model for studying the behavioral and physiological implications of a hyper-active HPA axis under normal and pathological conditions.

Measures of hypothalamic-pituitary-adrenal (HPA) axis activity such as increased diurnal cortisol levels or a blunted cortisol awakening response (CAR) have been associated with cognitive impairments in people with psychotic disorders. We aimed to explore whether there are sex differences in the relationship between HPA axis measures and cognition in early psychosis (EP).

An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and <5 years of illness; 16 subjects at risk for psychosis [high-risk, HR]) and a control group of 25 healthy subjects (HS). Dietary habits were examined by a dietician, who registered food intake (24h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes-Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis.

Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress-associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic-pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors.

Several studies performed in outbred Roman high- and low-avoidance lines (RHA and RLA, respectively) have demonstrated that the more anxious line (RLA) is characterized by a higher hypothalamic-pituitary-adrenal (HPA) response to certain stressors than the less anxious one (RHA). However, inconsistent results have also been reported. Taking advantage of the generation of an inbred colony of RLA and RHA rats (RHA-I and RLA-I, respectively), we have characterized in the two strains not only resting and stress levels of peripheral HPA hormones but also central components of the HPA axis, including CRF gene expression in extra-hypothalamic areas. Whereas resting levels of ACTH and corticosterone did not differ between the strains, a greater response to a novel environment was found in RLA-I as compared to RHA-I rats. RLA-I rats showed enhanced CRF gene expression in the paraventricular nucleus (PVN) of the hypothalamus, with normal arginin-vasopressin gene expression in both parvocellular and magnocellular regions of the PVN. This enhanced CRF gene expression is not apparently related to altered negative corticosteroid feedback as similar levels of expression of brain glucorticoid and mineralocorticoid receptors were found in the two rat strains. CRF gene expression tended to be higher in the central amygdala and it was significantly higher in the dorsal region of the bed nucleus of stria terminalis (BNST) of RLA-I rats, while no differences appeared in the ventral region of BNST. Considering the involvement of CRF and the BNST in anxiety and stress-related behavioral alterations, the present data suggest that the CRF system may be a critical neurobiological substrate underlying differences between the two rat strains.

Hypothalamic-pituitary-adrenal (HPA) axis alterations in at-risk mental states (ARMS) resemble those observed in established psychosis but are less consistent. We aimed to explore HPA axis abnormalities in both first-episode psychosis (FEP) and ARMS patients, while controlling for psychopathological symptoms. We studied 21 ARMS, 34 FEP patients and 34 healthy subjects. Clinical assessment included psychopathological symptoms (positive, negative, disorganized, excited and depressive symptoms) and stress measures. Saliva cortisol levels were determined at awakening, 30' and 60' post-awakening, 10:00 h, 23:00 h and 10:00 h on the day after the administration of 0.25 mg of dexamethasone, which occurred at 23:00 h. Three HPA axis measures were calculated: cortisol awakening response (CAR), cortisol diurnal slope and cortisol suppression ratio of the dexamethasone suppression test (DST). There were no significant differences between groups in HPA axis measures. However, when exploring the relationship between HPA axis measures and psychopathological symptoms, in ARMS subjects (but not FEP patients), a flatter cortisol slope was associated with more prominent negative symptoms, whereas a blunted CAR was associated with excited symptoms. Although no significant differences in HPA axis measures were found between diagnostic groups, subtle abnormalities in the CAR or circadian cortisol rhythmicity might be important for the phenotype of ARMS individuals.

Cognitive deficits are a core feature of serious mental illnesses such as schizophrenia, major depressive disorder (MDD) and bipolar disorder (BD) and are a common cause of functional disability. There is limited efficacy of pharmacological interventions for improving the cognitive deficits in these disorders. As pro-cognitive pharmacological treatments are lacking, hormones or drugs that target the endocrine system may become potential candidates for 'repurposing' trials aiming to improve cognition. We aimed to study whether treatment with drugs targeting the hypothalamic-pituitary-adrenal (HPA) axis and sex steroids can improve cognition in patients with schizophrenia, MDD or BD. A systematic search was performed using PubMed (Medline), PsychInfo and clinicaltrials.gov, and a narrative synthesis was included. The systematic review identified 12 studies dealing with HPA-related drugs (mifepristone [n = 3], cortisol synthesis inhibitors [ketoconazole, n = 2], dehydroepiandrosterone [n = 5], fludrocortisone [n = 2]) and 14 studies dealing with sex steroids (oestradiol [n = 2], selective oestrogen receptor modulators [raloxifene, n = 7], pregnenolone [n = 5]). Positive trials were found for BD (mifepristone), MDD (dehydroepiandrosterone and fludrocortisone) and schizophrenia (dehydroepiandrosterone, raloxifene and pregnenolone). A replication of positive findings by at least two clinical trials was found for mifepristone in BD and raloxifene and pregnenolone in schizophrenia. The use of drugs targeting hormones related to the HPA axis and sex steroids is a promising field of research that might help to improve the cognitive outcome of patients with schizophrenia, bipolar disorder and major depressive disorder in the near future.

Glucose abnormalities and cognitive alterations are present before the onset of schizophrenia. We aimed to study whether glucose metabolism parameters are associated with cognitive functioning in recent-onset psychosis (ROP) patients while adjusting for hypothalamic-pituitary adrenal (HPA) axis measures.

The aim of this study was to evaluate, in male Long-Evans rats, whether a restricted-cafeteria diet (CAFR), based on a 30% calorie restriction vs continuous ad libitum cafeteria (CAF) fed animals, administered alone or in combination with moderate treadmill exercise (12 m/min, 35 min, 5 days/week for 8 weeks), was able to ameliorate obesity and the associated risk factors induced by CAF feeding for 18 weeks and to examine the changes in circadian locomotor activity, hypothalamic-pituitary-adrenal (HPA) axis functionality, and stress response elicited by this dietary pattern. In addition to the expected increase in body weight and adiposity, and the development of metabolic dysregulations compatible with Metabolic Syndrome, CAF intake resulted in a sedentary profile assessed by the home-cage activity test, reduced baseline HPA axis activity through decreased corticosterone levels, and boosted exploratory behavior. Both CAFR alone and in combination with exercise reduced abdominal adiposity and hypercholesterolemia compared to CAF. Exercise increased baseline locomotor activity in the home-cage in all dietary groups, boosted exploratory behavior in STD and CAF, partially decreased anxiety-like behavior in CAF and CAFR, but did not affect HPA axis-related parameters.

The hypothalamic-pituitary-adrenal (HPA) axis is activated by a wide range of stimuli, including drugs. Here we report that in male rats, a dose of sodium butyrate (NaBu) that is typically used to inhibit histone deacetylation (1200 mg/kg) increased the peripheral levels of HPA hormones and glucose. In a further experiment, we compared the effects of two different doses of NaBu (200 and 1200 mg/kg) and equimolar saline solutions on peripheral neuroendocrine markers and brain c-Fos expression to demonstrate a specific stress-like effect of NaBu that is not related to hypertonicity and to localise putatively involved brain areas. Only the high dose of NaBu increased the plasma levels of stress markers. The equimolar (hypertonic) saline solution also activated the HPA axis and the c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN), a key area for the control of the HPA axis, but the effects were of a lower magnitude than those of NaBu. Regarding other brain areas, group differences in c-Fos expression were not observed in the medial prefrontal cortex or the medial amygdala, but they were observed in the central amygdala and the lateral ventral septum. However, only the latter area of the NaBu group showed enhanced c-Fos expression that was significantly higher than that after hypertonic saline. The present data indicate that high doses of NaBu appear to act as a pharmacological stressor, and this fact should be taken into account when using this drug to study the role of epigenetic processes in learning and emotional behaviour.

Exposure to stress during childhood and adolescence increases vulnerability to developing several psychopathologies in adulthood and alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the prototypical stress system. Rodent models of juvenile stress appear to support this hypothesis because juvenile stress can result in reduced activity/exploration and enhanced anxiety, although results are not always consistent. Moreover, an in-depth characterization of changes in the HPA axis is lacking. In the present study, the long-lasting effects of juvenile stress on adult behavior and HPA function were evaluated in male rats. The juvenile stress consisted of a combination of stressors (cat odor, forced swim and footshock) during postnatal days 23-28. Juvenile stress reduced the maximum amplitude of the adrenocorticotropic hormone (ACTH) levels (reduced peak at lights off), without affecting the circadian corticosterone rhythm, but other aspects of the HPA function (negative glucocorticoid feedback, responsiveness to further stressors and brain gene expression of corticotrophin-releasing hormone and corticosteroid receptors) remained unaltered. The behavioral effects of juvenile stress itself at adulthood were modest (decreased activity in the circular corridor) with no evidence of enhanced anxiety. Imposition of an acute severe stressor (immobilization on boards, IMO) did not increase anxiety in control animals, as evaluated one week later in the elevated-plus maze (EPM), but it potentiated the acoustic startle response (ASR). However, acute IMO did enhance anxiety in the EPM, in juvenile stressed rats, thereby suggesting that juvenile stress sensitizes rats to the effects of additional stressors.