Changes In Neuroendocrine Function Research Articles

Additive, Common, and Cumulative Contributions of Stress on Diurnal Cortisol Activity: Evidence Among Latino College Students

The transition to college is a major socio-contextual shift marked by opportunity and stress. Adolescents who encounter significant stress during this time may experience changes in neuroendocrine function, an identified mechanism underlying associations between stress and psychopathology. Latino students may be particularly at-risk for stress exposure, as ethnic/racial minority youth experience both minority-specific and general life stressors. This study employed a “multi-risk model” to examine additive, common, and cumulative effects of various stressors on Latino college students’ diurnal cortisol. 180 Latino college students (Mage=18.95; 64.4% female) provided five saliva samples a day across three weekdays (M=14.88, SD=.95; 2,667 samples) to assess diurnal cortisol patterns (i.e., cortisol awakening response (CAR), diurnal cortisol slope (DCS)). Participants self-reported on multiple stress forms (general, academic, social, financial, bicultural, discrimination) via online survey and daily diary. Common and cumulative stress were assessed via exploratory factor analysis and cumulative risk index, respectively. Three-level growth curve models were fit using Mplus. In the additive model, general stress was associated with a flatter DCS (γ=.01, p=.03) and bicultural stress was linked with a steeper DCS (γ=-.07, p=.047). In the common model, college stress was related to a lower CAR (γ=-.09, p=.045). Higher cumulative stress was linked with a lower CAR (γ=-.06, p=.007). Findings highlight the physiological correlates of various stressors experienced by Latino college students. Results have implications for equity promoting interventions to reduce stress and subsequent physiological processes underlying the development of psychopathology.

The roles of DNA methylation and hydroxymethylation at short interspersed nuclear elements in the hypothalamic arcuate nucleus during puberty

Puberty is the gateway to adult reproductive competence, encompassing a suite of complex, integrative, and coordinated changes in neuroendocrine functions. However, the regulatory mechanisms of transcriptional reprogramming in the arcuate nucleus (ARC) during onset of puberty are still not fully understood. To understand the role of epigenetics in regulating gene expression, mouse hypothalamic ARCs were isolated at 4 and 8 weeks, and the transcriptome, DNA hydroxymethylation, DNA methylation, and chromatin accessibility were assessed via RNA sequencing (RNA-seq), reduced representation bisulfite sequencing (RRBS-seq), reduced representation hydroxymethylation profiling (RRHP)-seq, and assay for transposase-accessible chromatin (ATAC-seq), respectively. The overall DNA hydroxymethylation and DNA methylation changes in retroelements (REs) were associated with gene expression modeling for puberty in the ARC. We focused on analyzing DNA hydroxymethylation and DNA methylation at two short interspersed nuclear elements (SINEs) located on the promoter of the 5-hydroxytryptamine receptor 6 (Htr6) gene and the enhancer of the KISS-1 metastasis suppressor (Kiss1) gene and investigated their regulatory roles in gene expression. Our data uncovered a novel epigenetic mechanism by which SINEs regulate gene expression during puberty.

Stress hormones mediate developmental plasticity in vertebrates with complex life cycles

The environment experienced by developing organisms can shape the timing and character of developmental processes, generating different phenotypes from the same genotype, each with different probabilities of survival and performance as adults. Chordates have two basic modes of development, indirect and direct. Species with indirect development, which includes most fishes and amphibians, have a complex life cycle with a free-swimming larva that is typically a growth stage, followed by a metamorphosis into the adult form. Species with direct development, which is an evolutionarily derived developmental mode, develop directly from embryo to the juvenile without an intervening larval stage. Among the best studied species with complex life cycles are the amphibians, especially the anurans (frogs and toads). Amphibian tadpoles are exposed to diverse biotic and abiotic factors in their developmental habitat. They have extensive capacity for developmental plasticity, which can lead to the expression of different, adaptive morphologies as tadpoles (polyphenism), variation in the timing of and size at metamorphosis, and carry-over effects on the phenotype of the juvenile/adult. The neuroendocrine stress axis plays a pivotal role in mediating environmental effects on amphibian development. Before initiating metamorphosis, if tadpoles are exposed to predators they upregulate production of the stress hormone corticosterone (CORT), which acts directly on the tail to cause it to grow, thereby increasing escape performance. When tadpoles reach a minimum body size to initiate metamorphosis they can vary the timing of transformation in relation to growth opportunity or mortality risk in the larval habitat. They do this by modulating the production of thyroid hormone (TH), the primary inducer of metamorphosis, and CORT, which synergizes with TH to promote tissue transformation. Hypophysiotropic neurons that release the stress neurohormone corticotropin-releasing factor (CRF) are activated in response to environmental stress (e.g., pond drying, food restriction, etc.), and CRF accelerates metamorphosis by directly inducing secretion of pituitary thyrotropin and corticotropin, thereby increasing secretion of TH and CORT. Although activation of the neuroendocrine stress axis promotes immediate survival in a deteriorating larval habitat, costs may be incurred such as reduced tadpole growth and size at metamorphosis. Small size at transformation can impair performance of the adult, reducing probability of survival in the terrestrial habitat, or fecundity. Furthermore, elevations in CORT in the tadpole caused by environmental stressors cause long term, stable changes in neuroendocrine function, behavior and physiology of the adult, which can affect fitness. Comparative studies show that the roles of stress hormones in developmental plasticity are conserved across vertebrate taxa including humans.

Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression

Postpartum depression (PPD) affects up to 20% of mothers and has negative consequences for both mother and child. Although exposure to psychosocial stress during pregnancy and abnormalities in the hypothalamic pituitary adrenal (HPA) axis have been linked to PPD, molecular changes in the brain that contribute to this disease remain unknown. This study utilized a novel chronic psychosocial stress paradigm during pregnancy (CGS) to investigate the effects of psychosocial stress on maternal behavior, neuroendocrine function, and gene expression changes in molecular regulators of the HPA axis in the early postpartum period. Postpartum female mice exposed to CGS display abnormalities in maternal behavior, including fragmented and erratic maternal care patterns, and the emergence of depression and anxiety-like phenotypes. Dysregulation in postpartum HPA axis function, evidenced by blunted circadian peak and elevation of stress-induced corticosterone levels, was accompanied by increased CRH mRNA expression and a reduction in CRH receptor 1 in the paraventricular nucleus of the hypothalamus (PVN). We further observed decreased PVN expression of nuclear steroid hormone receptors associated with CRH transcription, suggesting these molecular changes could underlie abnormalities in postpartum HPA axis and behavior observed. Overall, our study demonstrates that psychosocial stress during pregnancy induces changes in neuroendocrine function and maternal behavior in the early postpartum period and introduces our CGS paradigm as a viable model that can be used to further dissect the molecular defects that lead to PPD.

Latino adolescents’ cultural values associated with diurnal cortisol activity

Hypothalamic-pituitary-adrenal (HPA) axis activity has been identified as a mechanism through which daily life stress contributes to health problems and racial/ethnic health disparities. Stress-related changes in neuroendocrine function are evident as early as adolescence, but the ways in which promotive cultural factors may also contribute to variation in diurnal HPA activity have received little empirical attention. Grounded in cultural models of resilience, dual dimensions of Latino adolescents’ cultural values (ethnic heritage and U.S. mainstream) were examined as promotive and protective factors in relation to their diurnal salivary cortisol patterns using ecological momentary assessment (N = 209; Mage = 18.10; 64.4% female). Participants provided 5 daily saliva samples for 3 days while completing corresponding electronic diary reports and using time-sensitive compliance devices (track caps, actigraphs). Results from 3-level growth curve models indicated that higher U.S. mainstream cultural values (e.g., self-reliance, competition, material success) were associated with higher average waking cortisol levels and a more rapid rate of diurnal cortisol decline (i.e., “steeper” slope). Regarding situational deviations from the diurnal rhythm (within-person differences), cortisol levels were higher in relation to diary-reported ongoing stress (vs. completed). Accounting for these situational differences in stress timing, a cross-level interaction (i.e., between-person difference in within-person process) indicated that higher perceived stress than usual was associated with lower cortisol levels for adolescents with stronger alignment to Latino ethnic heritage values (e.g., familism, respect, religiosity), compared to relatively higher cortisol levels for those with less alignment to these values. Results were consistent adjusting for participants’ sex, immigrant generation, parents’ education level, depressive symptoms, medication use, sleep duration, and other self-reported health behaviors. These findings join the growing science of cultural neurobiology by demonstrating the promotive and potentially regulating influence of cultural values in the daily HPA functioning of Latino adolescents.

Changes in GABAergic Transmission to and Intrinsic Excitability of Gonadotropin-Releasing Hormone (GnRH) Neurons during the Estrous Cycle in Mice.

Gonadotropin-releasing hormone (GnRH) neurons form the final common central output pathway controlling fertility and are regulated by steroid feedback. In females, estradiol feedback action varies between negative and positive; negative feedback typically regulates episodic GnRH release whereas positive feedback initiates a surge of GnRH, and subsequently luteinizing hormone (LH) release ultimately triggering ovulation. During the estrous cycle, changes between estradiol negative and positive feedback occur with cycle stage and time of day, with positive feedback in the late afternoon of proestrus in nocturnal species. To test the hypotheses that synaptic and intrinsic properties of GnRH neurons are regulated by cycle stage and time of day, we performed whole-cell patch-clamp studies of GnRH neurons in brain slices from mice at two times considered negative feedback (diestrous PM and proestrous AM) and during positive feedback (proestrous PM). GABAergic transmission can excite GnRH neurons and was higher in cells from proestrous PM mice than cells from proestrous AM mice and approached traditional significance levels relative to cells from diestrous PM mice. Action potential response to current injection was also greater in cells from proestrous PM mice than the other two groups. Interestingly, the hormonal milieu of proestrous AM provided stronger negative feedback on both GnRH neuron excitability and GABAergic postsynaptic current (PSC) amplitude than diestrous PM. These observations demonstrate elements of both synaptic and intrinsic properties of GnRH neurons are regulated in a cycle-dependent manner and provide insight into the neurobiological mechanisms underlying cyclic changes in neuroendocrine function among states of estradiol negative and positive feedback.

Adolescent chronic stress causes hypothalamo–pituitary–adrenocortical hypo-responsiveness and depression-like behavior in adult female rats

Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposure to 14 days of chronic variable stress (CVS) in late-adolescent (pnd 45–58) female rats on neuroendocrine function, neuropeptide mRNA expression and depressive-like behavior in adolescence (pnd 59) and in adulthood (pnd 101). Adult females exposed to CVS in adolescence have a blunted hypothalamo-pituitary-adrenocortical (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN), suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test, despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Overall, our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior, potentially altering the developmental trajectory of stress circuits as female rats age into adulthood.

Trait Anxiety Moderates the Relationship Between Testosterone Responses to Competition and Aggressive Behavior

Testosterone (T) concentrations change rapidly in the context of human competition, and these changes in neuroendocrine function may serve to modulate future aggressive behavior. However, an increase in T during competition does not translate into aggressive behavior among all individuals. Here, we examined the extent to which individual differences in trait anxiety moderate the relationship between T responses to competition and aggressive behavior. Across two studies, we found that T responses to competition were positively correlated with subsequent aggression, but only among men scoring relatively low in trait anxiety. Trait anxiety did not moderate the relationship between T reactivity and aggression in women. These findings highlight the importance of considering individual difference in trait anxiety when examining the neuroendocrine correlates of human aggression.

How postnatal insults may program development: studies in animal models.

During the postnatal period, the nervous system is modified and shaped by experience, in order to adjust it to the particular environment in which the animal will live. This plasticity, one of the most remarkable characteristics of the nervous system, promotes adaptive changes, but it also makes brain more vulnerable to insults. This chapter will focus on the effects of interventions during the postnatal development in animal models of neonatal handling (usually up to 15min of handling) and maternal separation (usually at least for 3h). Sex-specific changes and effects of prepubertal stress such as social isolation later on in life were also considered. These interventions during development induce long-lasting traces in the pups' nervous system, which will be reflected in changes in neuroendocrine functions, including the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axes; anxiety and cognitive performance; and feeding, sexual, and social behavior. These enduring changes may be adaptive or maladaptive, depending on the environment in which the animal will live. The challenge researchers facing now is to determine how to reverse the deleterious effects that may result from early-life stress exposure.

Stress-induced enhancement of fear conditioning activates the amygdalar cholecystokinin system in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD), a debilitating psychiatric disease characterized by invasive and persistent fear memories-induced stressful experience, is associated with numerous changes in neuroendocrine function. Here, we investigated whether PTSD-like symptoms are associated with changes in the cholecystokinin (CCK) system in the basolateral amygdala. We developed an animal model of PTSD using multiple foot shocks at 1.1 mA. The resulting conditioned fear response was severe (>80% freezing) and maintained for at least 28 days. The stress-associated neurotransmitters norepinephrine, dopamine, and corticotrophin-releasing hormone were elevated at 1 day after foot shock. CCK immunoreactivity and extracellular concentration as well as the expression of CCK receptors (CCK1R, CCK2R) increased progressively for 28 days following foot shock. Taken together, these results suggest that stress-induced activation of the CCK system in the BLA, which may contribute toward the development of PTSD-like symptoms.

On the causes of early life experience effects: Evaluating the role of mom

Early life experiences are thought to have long-lasting effects on cognitive, emotional, and social function during adulthood. Changes in neuroendocrine function, particularly the hypothalamic-pituitary-adrenal (HPA) axis, contribute to these systems-level behavioral effects. In searching for causal mechanisms underlying these early experience effects, pioneering research has demonstrated an important role for maternal care in offspring development, and this has led to two persistent ideas that permeate current research and thinking: first, environmental impact on the developing infant is mediated through maternal care behavior; second, the more care that a mother provides, the better off her offspring. While a good beginning, the reality is likely more complex. In this review, we critically examine these ideas and propose a computationally-motivated theoretical framework, and within this framework, we consider evidence supporting a hypothesis of maternal modulation. These findings may inform policy decisions in the context of child health and development.

Basal functioning of the hypothalamic-pituitary-adrenal (HPA) axis and psychological distress in recreational ecstasy polydrug users

Ecstasy (MDMA) is a psychostimulant drug which is increasingly associated with psychobiological dysfunction. While some recent studies suggest acute changes in neuroendocrine function, less is known about long-term changes in HPA functionality in recreational users. The current study is the first to explore the effects of ecstasy-polydrug use on psychological distress and basal functioning of the HPA axis through assessing the secretion of cortisol across the diurnal period. Seventy-six participants (21 nonusers, 29 light ecstasy-polydrug users, 26 heavy ecstasy-polydrug users) completed a substance use inventory and measures of psychological distress at baseline, then two consecutive days of cortisol sampling (on awakening, 30 min post awakening, between 1400 and 1600 hours and pre bedtime). On day 2, participants also attended the laboratory to complete a 20-min multitasking stressor. Both user groups exhibited significantly greater levels of anxiety and depression than nonusers. On day 1, all participants exhibited a typical cortisol profile, though light users had significantly elevated levels pre-bed. On day 2, heavy users demonstrated elevated levels upon awakening and all ecstasy-polydrug users demonstrated elevated pre-bed levels compared to non-users. Significant between group differences were also observed in afternoon cortisol levels and in overall cortisol secretion across the day. The increases in anxiety and depression are in line with previous observations in recreational ecstasy-polydrug users. Dysregulated diurnal cortisol may be indicative of inappropriate anticipation of forthcoming demands and hypersecretion may lead to the increased psychological and physical morbidity associated with heavy recreational use of ecstasy.

Sleep Apnea, Chronic Sleep Restriction, and Inflammation

Obstructive sleep apnea (OSA) and chronic sleep restriction can lead to adverse consequences on various organ systems, including cardiovascular, neuroendocrine, and immune. There are bidirectional relationships among OSA, chronic sleep restriction, and the metabolic syndrome. Several mechanisms are responsible for these relationships, including intermittent hypoxia, systemic inflammation, activation of the sympathetic nervous system, and changes in neuroendocrine function. Intermittent hypoxia and systemic inflammation also play central roles in endothelial dysfunction and accelerated atherosclerosis associated with both OSA and chronic sleep restriction.

Euglycemic Agent-mediated Hypothalamic Transcriptomic Manipulation in the N171–82Q Model of Huntington Disease Is Related to Their Physiological Efficacy

Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171-82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD.

Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet

Short-term energy deprivation reduces leptin concentrations and alters the levels of circulating hormones of the hypothalamic-pituitary-peripheral axis in lean subjects. Whether the reduction in leptin concentration during long-term weight loss in obese individuals is linked to the same neuroendocrine changes seen in lean, leptin-sensitive subjects remains to be fully clarified. In this study, 24 overweight and obese adults (16 women and eight men; body mass index (BMI): 27.5-38.0 kg/m(2)) were prescribed a hypocaloric diet (-500 kcal/day) and were randomized to receive recombinant methionyl leptin (n=18, metreleptin, 10 mg/day self-injected s.c.) or placebo (n=6, same volume and time as metreleptin) for 6 months. Metreleptin administration did not affect weight loss beyond that induced by hypocaloric diet alone (P for interaction=0.341) but increased the serum concentrations of total leptin by six- to eight-fold (P<0.001) and led to the generation of anti-leptin antibodies. Despite free leptin concentration (P for interaction=0.041) increasing from 9±1 ng/ml at baseline to 43±15 and 36±12 ng/ml at 3 and 6 months, respectively, changes in circulating hormones of the thyroid and IGF axes at 3 and 6 months were not significantly different in the placebo- and metreleptin-treated groups. Leptin does not likely mediate changes in neuroendocrine function in response to weight loss induced by a mild hypocaloric diet in overweight and obese subjects.

Single prolonged stress decreases glutamate, glutamine, and creatine concentrations in the rat medial prefrontal cortex

Application of single prolonged stress (SPS) in rats induces changes in neuroendocrine function and arousal that are characteristic of post traumatic stress disorder (PTSD). PTSD, in humans, is associated with decreased neural activity in the prefrontal cortex, increased neural activity in the amygdala complex, and reduced neuronal integrity in the hippocampus. However, the extent to which SPS models these aspects of PTSD has not been established. In order to address this, we used high-resolution magic angle spinning proton magnetic resonance spectroscopy (HR-MAS 1H MRS) ex vivo to assay levels of neurochemicals critical for energy metabolism (creatine and lactate), excitatory (glutamate and glutamine) and inhibitory (gamma amino butyric acid (GABA)) neurotransmission, and neuronal integrity (N-acetylaspartate (NAA)) in the medial prefrontal cortex (mPFC), amygdala complex, and hippocampus of SPS and control rats. Glutamate, glutamine, and creatine levels were decreased in the mPFC of SPS rats when compared to controls, which suggests decreased excitatory tone in this region. SPS did not alter the neurochemical profiles of either the hippocampus or amygdala. These data suggest that SPS selectively attenuates excitatory tone, without a disruption of neuronal integrity, in the mPFC.

Zentrale Schmerzverarbeitung bei funktionellen somatischen Syndromen

Functional pain syndromes usually are characterized by a local or generalized increase in pain sensitivity, spontaneous ongoing pain, and a variety of other common symptoms. Classification or definition of a syndrome is usually somewhat arbitrarily based on the predominantly affected body region or a main symptom, resulting in significant overlap between conditions. Support for the involvement of the central nervous system (CNS) comes from the frequent comorbidity of affective disorders and symptomatology, disturbances in cognitive function, changes in neuroendocrine function, and dysregulation of the autonomic nervous system, although only subgroups of patients are affected. Findings of neuroimaging studies in functional pain syndromes typically reveal plausible correlates for the patients' subjective complaints and indicate a central augmentation in pain processing but also in other sensory systems including a postulated interoceptive system. The pathophysiology of this augmentation is not clear, and the importance of peripheral input remains unresolved, as well as the contribution of spinal and supraspinal mechanisms. Affective and cognitive factors clearly influence pain processing in these syndromes, but do not fully explain the observed augmentation. For FMS, chronic low back pain, and irritable bowel syndrome a dysfunction of the descending inhibitory systems is supported by these findings. However, longitudinal studies are needed to confirm the causality of the reported associations and to establish a primary role of the CNS in these syndromes. Current techniques like VBM and H-MRS have revealed potential yet highly variable structural abnormalities of the CNS in several of the syndromes, but clinical relevance and conclusions from these studies remain far from clear. New theoretical concepts should drive prospective and interdisciplinary research based on well-defined hypotheses to use the full potential of the current neuroimaging techniques.

Consequences of post-weaning social isolation on anxiety behavior and related neural circuits in rodents

Exposure to adverse experiences in early-life is implicated in the later vulnerability to development of psychiatric disorders, including anxiety and affective disorders in humans. Adverse early-life experiences likely impart their long-term consequences on mental health by disrupting the normal development of neural systems involved in stress responses, emotional behavior and emotional states. Neural systems utilizing the neurotransmitters serotonin, dopamine and the neuropeptide corticotropin-releasing factor (CRF) are implicated in mediating emotive behaviors, and dysfunction of these neurochemical systems is associated with mood/anxiety disorders. These neural systems continue maturing until early or mid-adolescence in humans, thus alterations to their development are likely to contribute to the long-term consequences of adverse early-life experiences. A large body of literature suggests that post-weaning isolation rearing of rodents models the behavioral consequences of adverse early-life experiences in humans. Overall, the majority findings suggest that post-weaning social isolation that encompasses pre-adolescence produces long-lasting alterations to anxiety behavior, while measures of monoaminergic activity in various limbic regions during social isolation suggest alterations to dopamine and serotonin systems. The goal of this review is to evaluate and integrate findings from post-weaning social isolation studies specifically related to altered fear and anxiety behaviors and associated changes in neuroendocrine function and the activity of monoaminergic systems.

Childhood Parental Loss and Adult Hypothalamic-Pituitary-Adrenal Function

Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function that could predispose to the development of psychiatric disorders. Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared with a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, parental care, gender, and age on the hormone responses to the Dex/CRH test. Parental loss was associated with increased cortisol responses to the test, particularly in men. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. Adrenocorticotropic hormone responses to the Dex/CRH test did not differ significantly as a function of parental loss. These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function.

Intracerebroventricular Administration of Corticotrophin‐Releasing Hormone Receptor Antagonists Produces Different Effects on Hypothalamic Pituitary Adrenal Responses to Novel Restraint Depending on the Stress History of the Animal

Corticotrophin-releasing hormone (CRH) regulates acute stress-induced changes in neuroendocrine function and behaviour. However, little is known about CRH functions in animals that have prior experience with repeated stress. Repeatedly-stressed rats exhibit a habituated hypothalamic-pituitary-adrenal (HPA) response to a familiar, homotypic stressor but exhibit maintained or enhanced HPA responses to a novel, heterotypic stressor. We examined the effects of intracerebroventricular (i.c.v.) administration of two different nonselective CRH receptor antagonists, alpha-helical CRH(9-41) (ahCRH) or D-Phe CRH(12-41) (D-PheCRH), on HPA responses to acute restraint in rats previously exposed to repeated cold stress (i.e. facilitated responses). Antagonists were administered as single i.c.v. injections prior to restraint to provide a general index of CRH function in control versus repeatedly-stressed rats. CRH receptor blockade with either ahCRH or D-PheCRH produced different effects on HPA responses to novel restraint depending on whether the animal had been previously cold stressed or not. Interestingly, some agonist-type effects were observed but only in repeatedly-stressed rats. In summary, these results indicate that manipulations of the CRH receptor have different effects on HPA activity depending on the stress history of the animal.