Sex, Pramipexole and Tiagabine Affect Behavioral and Hormonal Response to Traumatic Stress in a Mouse Model of PTSD

Posttraumatic stress disorder (PTSD) has been associated with abnormal regulation of the hypothalamic-pituitary-adrenal gland axis (HPA). Women demonstrate a more robust HPA response and are twice as likely to develop PTSD than men. The role of sex hormones in PTSD remains unclear. We investigated whether post-trauma chronic treatment with the GABA-ergic agent tiagabine and dopamine-mimetic pramipexole affected the behavioral outcome and plasma levels of corticosterone, testosterone, or 17β-estradiol in female and male mice. These medications were investigated due to their potential capacity to restore GABA-ergic and dopaminergic deficits in PTSD. Animals were exposed to a single prolonged stress procedure (mSPS). Following 13 days treatment with tiagabine (10 mg/kg) or pramipexole (1 mg/kg) once daily, the PTSD-like phenotype was examined in the fear conditioning paradigm. Plasma hormones were measured almost immediately following the conditioned fear assessment. We report that the exposure to mSPS equally enhanced conditioned fear in both sexes. However, while males demonstrated decreased plasma corticosterone, its increase was observed in females. Trauma elevated plasma testosterone in both sexes, but it had no significant effects on 17β-estradiol. Behavioral manifestation of trauma was reduced by pramipexole in both sexes and by tiagabine in females only. While neither compound affected corticosterone in stressed animals, testosterone levels were further enhanced by tiagabine in females. This study shows sex-dependent efficacy of tiagabine but not pramipexole in a mouse model of PTSD-like symptoms and a failure of steroid hormones’ levels to predict PTSD treatment efficacy.

Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

Adrenal Insufficiency in Neurocritically Ill Patients

The hypothalamic-pituitary-adrenal (HPA) axis is a complex system that equilibrates blood levels of glucocorticoid hormones. Cortisol levels are dynamic and normally fluctuate in response to constant feedback; functional deficiency in this system results in adrenal insufficiency (AI). An elevated corticosteroid level is needed as a protective response to stress during acute illness or major surgery, but corticosteroid secretion can be altered by splanchnic and central nervous system influence, fever, acidosis, and proinflammatory cytokines. Critical illness–related corticosteroid insufficiency (CIRCI) is a relatively insufficient HPA response; often encountered in critical care patients, it can worsen outcomes.

Milk cortisol response to group relocation in lactating cows

The aim of the study reported in this Research Communication was to analyse the variations of milk cortisol concentrations in response to the relocation of dairy cows between production groups. Milk cortisol measured during 3 consecutive days did not vary significantly in cows without environmental perturbation. However, relocation of cows caused a significant increase of cortisol in milk starting from the first milking after the group change. This suggests that cortisol in milk can be a suitable biomarker to assess the HPA response of dairy cows to a short/medium-term environmental challenge.

Attachment Style And Cortisol Response To Psychosocial Stress In Eating Disorder Patients

IntroductionStress exposure is a risk factor for both the onset and the maintenance of Eating Disorders (EDs). The attachment theory may provide a framework to explain the relationship between social stress and EDs, since secure attachment promotes the seeking for support in order to help people to face stressful events. The endogenous stress response system, including the hypothalamus-pituitary-adrenal (HPA) axis, is likely involved in mediating the role of attachment in the subjects’ coping with stressful situations.Objectives and aimsWe explored cortisol responses to the Trier Social Stress Test (TSST) of patients with EDs in order to evaluate possible associations between subjects’ attachment styles and HPA axis functioning.MethodsTwenty-one adult patients with EDs (7 with secure attachment and 14 with insecure attachment) filled in the Experience in Close Relationship (ECR) questionnaire, which assesses the adult attachment style, and were exposed to the TSST. Saliva samples were collected before and after the stress in order to measure cortisol levels.ResultsAs compared to ED patients with secure attachment, those with insecure attachment showed a significant different pattern of the HPA response to the stress test.DiscussionPresent findings suggest that attachment style may influence the HPA response to stress in patients with EDs and this effect may have relevant implications for the pathophysiology of EDs.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Adaptive Changes in Basal and Stress-Induced HPA Activity in Lactating and Post-Lactating Female Rats

Lactation represents a period of marked adaptation of the hypothalamo–pituitary–adrenal HPA axis. We characterized basal and stress-induced HPA activity during lactation and experimental weaning using dynamic blood sampling in rats. Pulsatile and diurnal corticosterone release occurred at all reproductive stages studied (virgin; day 10 of lactation; 3 and 14 days after experimental weaning on day 10 of lactation). However, in lactating rats the diurnal peak was significantly reduced, resulting in a flattened rhythm, and three days after weaning, basal HPA activity was markedly suppressed: the number of pulses and underlying basal levels of corticosterone were reduced and the diurnal rise phase delayed. Marked changes in the HPA response to 10 min noise stress also occurred at these times: being completely absent in lactating animals, but restored and highly prolonged in early weaned animals. Injection of methylprednisolone (2 mg, iv) was used to determine whether changes in fast glucocorticoid suppression correlated with these adaptive changes. Methylprednisolone induced a rapid suppression of corticosterone in virgin animals, but this effect was markedly attenuated in lactating and early weaned animals and was accompanied by significant changes in relative expression of hippocampal glucocorticoid and mineralocorticoid receptor mRNA. All effects were reversed or partially reversed 14 days after experimental weaning. Thus, the presence of the pups has an important influence on regulation of the HPA axis, and while postpartum adaptations are reversible, acute weaning evokes marked reorganisation of basal and stress-induced HPA activity.