Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer's disease.

BACKGROUND: Increased basal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been repeatedly demonstrated in Alzheimer's disease (AD), and some studies suggest increased basal activity of the sympathetic nervous system (SNS) in this disorder; however, the effects of AD on HPA axis or SNS responses to a standardized aversive stressor have not been examined. The neuroendocrine response to aversive stress may be relevant to the pathophysiology of AD. METHODS: Plasma adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine responses to a 1-min cold pressor test (CPT) were measured in nine medically healthy AD outpatients (age 76 +/- 2 years) and nine age- and gender-matched medically healthy cognitively normal older subjects (age 76 +/- 1 year). RESULTS: The cortisol response to CPT was increased in the AD group but the ACTH response did not differ between groups. Basal NE concentrations were higher in the AD group. Although NE responses to CPT did not differ between groups, the blood pressure response to CPT was higher in the AD subjects. CONCLUSIONS: These results suggest increased HPA axis responsiveness to CPT at the level of the adrenal cortex in AD. The results also suggest increased basal sympathoneural activity and increased cardiovascular responsiveness to sympathoneural stimulation in AD under the conditions of this experimental protocol. Increased SNS stimulatory modulation of the adrenal cortex is a possible mechanism contributing to the observed enhanced cortisol response to CPT in these AD subjects.     

Recovery of the hypothalamic-pituitary-adrenal axis from suppression by short-term, high-dose intravenous prednisolone therapy in patients with MS

We have studied the recovery of the hypothalamic-pituitary-adrenal (HPA) axis from inhibition by short-term, intravenous high-dose, corticosteroid therapy (IVHDCT) without subsequent oral replacement therapy in 10 patients with relapsing-remitting or progressive multiple sclerosis (MS) using the human corticotrophin-releasing hormone (hCRH) test. There was significant HPA suppression with profoundly decreased basal and peak plasma ACTH and cortisol levels 24 h after cessation of therapy. However, at 48 h the pituitary response was greatly enhanced with peak ACTH concentrations rising by more than 100 % over baseline values in 7 of 10 patients. Basal and stimulated ACTH concentrations returned to pre-treatment levels at 120 h. Basal and stimulated plasma cortisol levels remained subnormal in 6 patients 120 h after IVHDCT. We conclude that IVHDCT without oral replacement therapy in MS patients is endocrinologically safe.     

Catecholamine and cortisol levels during sleep in women with irritable bowel syndrome

Abstract  Evidence suggests that patients with irritable bowel syndrome (IBS) are hyper-responsive to environmental, physical and visceral stimuli. IBS patients also frequently report poor sleep quality. This study compared serum cortisol and plasma catecholamine levels during sleep between women with IBS ( n  = 30) and healthy controls ( n  = 31), and among subgroups within the IBS sample based on predominant stool patterns, IBS-diarrhoea ( n  = 14), IBS-constipation ( n  = 7) and IBS-alternators ( n  = 9). Cortisol was measured from serial blood samples drawn every 20 min, and catecholamines every hour, in a sleep laboratory from 8  pm until awakening. Because of the varied sleep schedules of the individual participants, each subject's hormone series time base was referenced with respect to their onset of Stage 2 sleep. Overall, there were no significant differences in cortisol or catecholamine patterns between women with IBS and controls, nor were there any group by time interactions. However, women with constipation-predominant IBS demonstrated significantly increased noradrenaline, adrenaline and cortisol levels throughout the sleep interval, and women with diarrhoea-predominant IBS were significantly lower on noradrenaline and cortisol. These results suggest that differences in neuroendocrine levels during sleep among IBS predominant bowel pattern subgroups may be greater than differences between IBS women and controls. Neuroendocrine profiles during sleep may contribute to our understanding of symptom expression in IBS.     

Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome

OBJECTIVE: Subtle dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis have been proposed as an underlying pathophysiological mechanism in chronic fatigue syndrome (CFS). This study attempted to assess the relationship between patient characteristics and HPA axis functioning using a neuroendocrine challenge test. METHOD: A test battery designed to assess different dimensions of CFS was given to 18 CFS patients and 17 controls. To evaluate the integrity of the HPA axis, the Insulin Tolerance Test (ITT), a centrally acting neuroendocrine challenge test, was performed on patients and controls. ACTH, salivary free cortisol and total plasma cortisol levels were assessed as a measure of the HPA axis stress response. Correlations of patient characteristics were calculated with integrated responses for all endocrine parameters. RESULTS: CFS patients had a significantly reduced area under the ACTH response curve (AUC) in the ITT. The AUC was significantly associated with the duration of CFS symptoms (r = -.592, P = .005) and the severity of fatigue symptomatology (r = -.41, P = .045). In addition, duration of CFS was correlated with the severity of fatigue symptoms (r = .38, P = .045). Similar associations were not observed for cortisol parameters. CONCLUSION: It has been postulated that neuroendocrine dysregulations observed in CFS are of an acquired nature. The results of a strong association between the integrated ACTH response and the duration of CFS emphasizes the need to consider factors known to be risk factors for the chronicity of CFS symptoms, such as profound inactivity, deconditioning and sleep abnormalities, as possible candidates for secondary causes of neuroendocrine dysregulations in CFS.     

Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome

OBJECTIVE: It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in chronic fatigue syndrome, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls. METHOD: Twenty-one CFS patients and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha were assessed at baseline as well as 10 and 60 min after the stress test. RESULTS: CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly associated for TNF-alpha in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels. CONCLUSION: CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha.     

Anticipation of public speaking and sleep and the hypothalamic-pituitary-adrenal axis in women with irritable bowel syndrome

Background Evidence suggests that subgroups of patients with irritable bowel syndrome (IBS) are hyper‐responsive to a variety of laboratory stress conditions. Methods This study compared sleep quality and night time plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels in response to anticipation of public speaking between 43 women with IBS and 24 healthy control women. In addition, comparisons were made between subgroups within the IBS sample based on predominant stool patterns, 22 IBS‐constipation and 21 IBS‐diarrhea. Subjects slept three nights in a sleep laboratory, and on the third night serial blood samples were drawn every 20 min from 08:00 PM until awakening. As the subjects had different sleep onsets, each subject’s results were synchronized to the first onset of stage 2 sleep. Key Results Compared the healthy control group, women with IBS had significantly worse sleep efficiency, and higher cortisol but not ACTH levels over the night. However, there were no IBS bowel pattern subgroup differences. Among IBS subjects, cortisol levels early in the night were higher than found in our previous study with a similar protocol but without the threat of public speaking. These results suggest that a social stressor, such as public speaking prior to bedtime, increases cortisol but not ACTH levels suggesting HPA dysregulation in women with IBS. Conclusions & Inferences This response to a social stressor contributes to our understanding of the relationship of stress to symptom expression in IBS.     

Endocrine and cardiovascular responses to corticotropin-releasing hormone in patients with posttraumatic stress disorder: a role for atrial natriuretic peptide?

Hypothalamic-pituitary-adrenocortical (HPA) axis data, such as low plasma cortisol concentrations in spite of increased corticotropin-releasing hormone (CRH) levels in patients with posttraumatic stress disorder (PTSD), are difficult to interpret. Atrial natriuretic peptide (ANP) may be an explanatory link in the neuroendocrine pathophysiology of the disorder, since it is a neuromodulator with antianxiety effects that inhibits HPA activity at multiple levels. Seventeen patients with chronic PTSD and 17 healthy control subjects were given 100 microg of human CRH at 3 p.m. ANP, adrenocorticotropic hormone (ACTH), and cortisol levels in plasma as well as blood pressure and heart rate were measured during basal conditions and after CRH stimulation. Basal ANP levels were significantly lower in PTSD patients in comparison with normal controls, but the response to CRH was undistinguishable. In contrast to our expectation, no significant differences in basal or CRH-stimulated ACTH or cortisol parameters could be observed. Systolic and diastolic blood pressures at baseline and after CRH were significantly elevated in PTSD patients. All group differences remained significant after controlling for basal blood pressure and/or body mass index. Our data do not support a role of ANP in abnormal HPA axis regulation in PTSD. However, the persistently low ANP plasma levels in PTSD patients despite elevated blood pressure may serve to facilitate anxiety behavior and have adverse long-term cardiovascular consequences. Further studies to assess ANP secretion in PTSD patients and to clarify its pathophysiological impact are needed.     

Pre-experimental stress in patients with irritable bowel syndrome: high cortisol values already before symptom provocation with rectal distensions

Abstract  Stress is known to affect symptoms of irritable bowel syndrome (IBS) probably by an alteration of visceral sensitivity. We studied the impact of maximal tolerable rectal distensions on cortisol levels in patients with IBS, chronic constipation and controls, and evaluated the effect of the experimental situation per se . In twenty-four IBS patients, eight patients with chronic constipation and 15 controls salivary cortisol was measured before and after repetitive maximal tolerable rectal balloon distensions and at similar times in their usual environment. Rectal sensitivity thresholds were determined. IBS patients but not controls and constipation patients had higher cortisol levels both before and after the experiment compared with similar times on an ordinary day in their usual environment ( P  = 0.0034 and 0.0002). There was no difference in salivary cortisol level before compared with after rectal distensions. The IBS patients had significantly lower thresholds for first sensation, urge and maximal tolerable distension than controls ( P  = 0.0247, 0.0001 and <0.0001) and for urge and maximal tolerable distension than patients with constipation ( P  = 0.006 and 0.013). IBS patients may be more sensitive to expectancy stress than controls and patients with constipation according to salivary cortisol. Rectal distensions were not associated with a further significant increase in cortisol levels.     

Childhood neglect and parental care perception in cocaine addicts: relation with psychiatric symptoms and biological correlates

Childhood neglect and poor child–parent relationships have been reported to increase substance use disorders susceptibility. Stressful environmental factors, including emotional neglect, could affect individual personality traits and mental health, possibly inducing stable changes in hypothalamic–pituitary–adrenal (HPA) axis and brain mono-amine function, in turn involved in addictive behavior vulnerability. Therefore, we decided to investigate homovanillic (HVA) and prolactin (PRL) plasma levels, as expression of possible changes in dopamine function, ACTH and cortisol plasma levels, as measures of HPA axis function, and concomitant psychiatric symptoms profile in abstinent cocaine addicts, in relationship to their childhood history of neglect and poor parental care perception.MethodsFifty abstinent cocaine dependent patients, and 44 normal controls, matched for age and sex, were submitted to a detailed psychiatric assessment (DSM IV criteria). All patients and controls completed the Symptoms Check List-90 (SCL-90) and the Buss Durkee Hostility Inventory (BDHI), to evaluate psychiatric symptoms frequency and aggressiveness levels. The Childhood Experience of Care and Abuse-Questionnaire (CECA-Q) and Parental Bonding Instrument (PBI) have been used to retrospectively investigate parent–child relationships. Blood samples were collected to determine HVA, PRL, ACTH and cortisol basal plasma levels.ResultsCocaine addicted individuals in general showed significantly lower HVA, and higher PRL, ACTH and cortisol basal levels respect to controls. In particular, neuroendocrine changes characterized cocaine addicts with childhood history of neglect and low perception of parental care. Obsessive–compulsive, depression and aggressiveness symptoms have been found related to poor parenting, inversely associated to HVA levels and directly associated to PRL, ACTH and cortisol levels.ConclusionsThese findings suggest the possibility that childhood experience of neglect and poor parent–child attachment may partially contribute to a complex neurobiological derangement including HPA axis and dopamine system dysfunctions, playing a crucial role in addictive and affective disorders susceptibility.     

Effects of mu, kappa, and delta opioid receptor agonists on the function of hypothalamic-pituitary-adrenal axis in monkeys

Opioids can modulate neuroendocrine function. Less is known about the involvement of opioid receptor subtypes in the stimulatory effects of opioids on the primate hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the stimulatory effects of opioids selective for each receptor subtype on plasma adrenocorticotropic hormone (ACTH) and cortisol levels in both male and female monkeys. The blood collection procedure was conducted in home-caged and unanesthetized rhesus monkeys that showed low and stable basal ACTH and cortisol levels. Three opioid receptor agonists, fentanyl, U-50488H, and SNC80, were used in behaviorally active doses; they are highly selective for mu, kappa, and delta opioid receptors, respectively. Plasma samples were collected at multiple time points before and after IV administration of each compound and were quantified by radioimmunoassay. Neither fentanyl (0.0003-0.02mg/kg) nor SNC80 (0.03-0.3mg/kg) changed either ACTH or cortisol basal levels. In contrast, U-50488H (0.01-1mg/kg) dose-dependently stimulated ACTH and cortisol release in both male and female monkeys. Importantly, the stimulatory effects of U-50488H on the secretion of ACTH were blocked by a selective kappa opioid receptor antagonist, nor-Binaltorphimine. The antagonist effect of nor-binaltorphimine lasted up to 20 weeks. These results indicate that only synthetic kappa, but not mu or delta opioid receptor agonists stimulate HPA axis activity after acute administration in primates.     

Hyper-Reactive Hypothalamo-Pituitary-Adrenocortical Axis in Rats Bred for High Anxiety-Related Behaviour

Psychiatric patients suffering from anxiety disorders or endogenous depression exhibit increased activity in their hypothalamo-pituitary-adrenocortical (HPA) axis. Recently, two Wistar rat lines, bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze, were described as a unique psychopathological animal model (1). The present study focused on the HPA axis reactivity of HAB and LAB animals to an emotional stressor. Thus, adult male HAB and LAB animals, fitted with jugular vein catheters 5 days prior to the experiment, were exposed to an open arm of the elevated plus-maze for 5 min. Whereas basal levels of ACTH and corticosterone were similar in both lines, HAB rats showed higher plasma concentrations at 5 and 15 min following stressor exposure (both hormones and both time points: P<0.01 vs LAB). Furthermore, increased basal (P<0.05 vs LAB) and stimulated (P<0.01 vs LAB) prolactin concentrations in HAB rats were found. In contrast to ACTH, corticosterone and prolactin, plasma oxytocin and vasopressin levels did not differ between HAB and LAB animals; oxytocin, but not vasopressin, responding to open arm exposure with a significant increase in both lines (P<0.05). In conclusion, particularly due to the association between inborn anxiety and HPA axis hyper-reactivity, the HAB rat represents a promising animal model for further investigation of the relationship between emotional disturbance and neuroendocrine activity.     

Increased responsiveness of the hypothalamus-pituitary-adrenal (HPA) axis to stress in newborns with atopic disposition

In previous studies, atopic patients showed attenuated cortisol responses to psychosocial stress which is suggestive of a hyporeactive hypothalamus-pituitary-adrenal (HPA) axis in this patient group. Regarding the anti-inflammatory role of glucocorticoids, reduced responsiveness of the HPA axis under stress may be one potential explanation of stress-induced exacerbation of atopic symptoms. The present study evaluated whether hyporeactivity of the HPA axis is a feature related to the disposition of atopy rather than a consequence of an ongoing chronic allergic inflammatory process. Newborns with an atopic disposition (parental atopy; n=31) and without atopic disposition (no parental atopy; n=20) were recruited. To further assess atopic disposition, total IgE levels were determined in the cord blood of the neonates. Three days after birth, a blood sample was obtained by a heel prick which is part of a standard pediatric examination. Blood sampling by heel prick is well known to be a significant stressor resulting in activation of the HPA axis in newborns. Analysis of salivary cortisol indicated a significant increase of cortisol levels in the newborns after the stressor with a trend towards an elevated cortisol response in babies with a family history of atopy or with elevated levels of cord IgE (> or = 0.5 kU/l). Neonates with a positive parental atopic heritage and elevated cord IgE were found to show significantly elevated cortisol responses to the heel prick stress when compared to newborns without a parental atopic history and normal cord IgE values. Moreover, cord IgE levels were significantly correlated with basal cortisol levels and the cortisol response to the stressor. These findings suggest that atopic disposition in neonates is associated with altered responsiveness of the HPA axis to stress which may increase the vulnerability to develop manifestation of atopy in later life.     

Delta sleep-inducing peptide response to human corticotropin-releasing hormone (CRH) in major depressive disorder. Comparison with CRH-induced corticotropin and cortisol secretion

Twenty-four subjects (12 patients with major depressive disorder and 12 controls matched for sex and age) received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an iv bolus dose. Healthy subjects exhibited a slight, but sustained, increase of plasma delta sleep-inducing peptide (DSIP) concentrations, whereas a marked reduction of DSIP levels was found in depressives. Compared to controls, depressed patients showed a significant attenuation of corticotropin (ACTH) responses, whereas cortisol secretion in response to hCRH was normal. Basal DSIP and cortisol concentrations were highly correlated and were higher in depressives than in controls. Both were negatively correlated with the DSIP responses to hCRH. These findings are compatible with the hypothesis that hypothalamic-pituitary-adrenal (HPA) overactivity in the depressive state is primarily due to central hypersecretion of CRH and support the view of a modulatory function of DSIP in the complex regulatory mechanism of the HPA system and of its pathophysiological significance for aberrant HPA axis function in major depressive disorder.     

Changes in Sleep-Endocrine Activity after Growth Hormone-Releasing Hormone Depend on Time of Administration

When administered intravenously (i.v.) in a pulsatile mode during the first half of the night to young normal controls, growth hormone-releasing hormone (GHRH) results in increased growth hormone (GH) plasma levels and slow wave sleep (SWS) and blunted cortisol release. In the present study we investigated whether GHRH has the same effects when administered in the early morning. Seven normal young male volunteers had 2 sessions each in the sleep laboratory (23.00 to 10.00  h) during which the secretion of GH, cortisol and corticotropin (ACTH) and polygraphic recordings were monitored. Verum (4 bolus injections of 50  μg GHRH) or placebo were injected i.v. at 04.00, 05.00, 06.00 and 07.00  h. GHRH stimulated GH plasma levels significantly whereas cortisol and ACTH were not altered. In the sleep-electroencephalogram, only rapid-eye-movement density was decreased significantly during the period of active medication; all other sleep parameters were unaffected. We suggest that the physiological occurring high activity of the hypothalamic-pituitary-adrenocortical(HPA) system in the early morning prevents the effects of GHRH on cortisol plasma levels and SWS. Thus GHRH administered to healthy young men in the early morning hours has the same effect as GHRH administered during the first half of the night to patients with major depression who have HPA hyperactivity throughout the day.     

Cortisol and ACTH responses to psychosocial stress are modulated by corticosteroid binding globulin levels

The hypothalamus-pituitary-adrenal (HPA) axis is vital for an organisms' response to physiological and psychological stress. Cortisol, secreted upon activation of the HPA axis, impacts on physiological systems throughout the organism. Responses to cortisol are influenced and modified by a number of factors, including corticosteroid binding globulin (CBG) levels. A major part of circulating cortisol is bound to CBG and only the unbound fraction is thought to be biologically active. The aim of the present study was to examine the modulating effect of CBG levels on hormonal responses following psychosocial stress in women using oral contraceptives (n=115) and in medication-free men (n=93). In women, CBG levels were negatively associated with ACTH and salivary cortisol and positively with total cortisol levels following the TSST. In men, positive associations were observed between CBG and ACTH and total cortisol levels following the TSST. CBG is an important regulatory element of HPA axis response patterns; therefore, CBG levels have to be taken into account as a potential modifier of ACTH and cortisol responses to psychosocial and pharmacological stimulation. Investigations of the consequences of long-lasting OC intake on the neuroendocrine stress regulation in women might be warranted.     

Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression.

BACKGROUND: Major depressive disorder (MDD) is often complicated by anxiety symptoms, and anxiety disorders occur in approximately 30% of mood cases. This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal (HPA) axis response to stress in patients with MDD. METHODS: Untreated subjects with pure MDD (n = 15), MDD with comorbid anxiety disorders (n = 18), and pure anxiety disorders (n = 15) were recruited by advertising. Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 48). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for adrenocorticotropic hormone (ACTH) and cortisol assay. RESULTS: When all depressed patients (n = 33) were compared with their matched control subjects (n = 33), they showed a significantly greater ACTH response to the stressor; however, this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders. A similar but nonsignificant effect was observed in the cortisol response. Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST. All patient groups showed similar levels of TSST-induced anxiety. CONCLUSIONS: Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression.     

Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition

Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.     

Effect of repeat exposure on neuroendocrine and symptom responses to pentagastrin

The cholecystokinin (CCK-B) agonist pentagastrin stimulates dose-dependent release of adrenocorticotropin (ACTH) and cortisol in humans, likely via direct pharmacological action at pituitary CCK-B receptors. Pentagastrin also produces side effects, however, which may be experienced as novel or anxiety arousing and could contribute to ACTH release. Available data suggest that pentagastrin's activation of the hypothalamic-pituitary-adrenal (HPA) axis is unrelated to anxiety symptoms themselves, but novelty effects have not been examined in this model and do strongly activate this system in animals. To further explore the impact of novelty and anxiety symptoms on HPA responses, pentagastrin was administered twice to 12 subjects (six male, six female) under single-blind conditions. Repeat pentagastrin injection was associated with a slight habituation in the magnitude of symptom and HPA axis responses, but robust HPA and symptom responses were seen following both injections. No relationships were found between anxiety symptoms and HPA activity and the modest symptomatic and neuroendocrine habituation appeared to occur independently. Pentagastrin may release ACTH and cortisol through direct pharmacological action, perhaps enhanced on first exposure by psychologically mediated novelty effects. Novelty, per se, is not likely the primary mediator of the HPA response. This model may be useful for further study of cognitive-emotional modulators of HPA axis activity.     

Stereotaxic localization of corticosterone to the amygdala enhances hypothalamo-pituitary-adrenal responses to behavioral stress

The amygdala is involved in behavioral, autonomic, and neuroendocrine responses to stressful stimuli. The goal of the current study was to determine the effect of directly elevating glucocorticoids in the amygdala on hypothalamo-pituitary-adrenocortical (HPA) responses to the elevated plus maze, a behavioral stressor known to activate the amygdala. Micropellets (30 microg) of crystalline corticosterone or cholesterol (control) were implanted bilaterally at the dorsal margin of the CeA in male Wistar rats; vascular catheters were also placed at this time. Five days post-surgery, blood samples were drawn at 07:00 and 19:00 h to assess diurnal rhythm of plasma corticosterone. At 7 days post-implantation, rats were subjected to behavioral stress using an elevated plus maze and blood was collected 15 min prior to stress, and at 15, 45, and 90 min after the initiation of the stressor. Corticotropin releasing factor (CRF) and arginine vasopressin (AVP) mRNA levels were analyzed by in situ hybridization in the medial parvocellular division of the hypothalamic paraventricular nucleus (mpPVN) in corticosterone- and cholesterol-implanted rats either not exposed to the elevated plus maze (control) or 4 h post-behavioral stress. Localization of corticosterone to the amygdala had no effect on diurnal rhythm of corticosterone secretion. Behavioral stress significantly increased peak plasma corticosterone levels in both groups to a similar level. However, in the corticosterone implanted rats, plasma corticosterone concentrations at 45 and 90 min post-stress were significantly greater compared to control rats indicating a prolonged corticosterone response to behavioral stress. In non-stressed rats, corticosterone delivery to the amygdala elevated basal CRF mRNA in the mpPVN to levels similar to those observed post-stress in control animals; no further increase was observed in CRF mRNA following stress. Behavioral stress resulted in a significant elevation in CRF mRNA in cholesterol controls. Basal AVP mRNA levels were unaffected by corticosterone implants. AVP mRNA did not increase in cholesterol implanted rats in response to behavioral stress. However, AVP mRNA levels were higher in corticosterone implanted rats post stress compared to cholesterol treated controls. In conclusion, direct administration of corticosterone to the amygdala increases plasma corticosterone in response to a behavioral stressor without altering the diurnal rhythm in plasma corticosterone. Elevated basal levels of mpPVN CRF mRNA, and the induction of a mpPVN AVP mRNA response to the behavioral stressor implicate enhanced ACTH secretagogue expression in the increased HPA response to corticosterone modulation of amygdala function.     

Corticotropin-releasing factor test in melancholic patients in depressed state versus recovery: a comparative study

PURPOSE: Basal adrenocorticotropin hormone (ACTH) and cortisol levels and their response to corticotropin-releasing factor (CRF) test were studied in melancholic depressive patients in depressed state and recovery, and compared with healthy controls. METHODS: Fifty-four outpatients diagnosed with unipolar depressive disorder with melancholic features according to DSM-IV and 23 healthy controls were included in the study. The Structured Clinical Interview for DSM-IV (SCID-IV) was used for diagnosis. Twenty-nine patients were in recovery, while 25 were in depressed state at the moment of the administration of the CRF test. FINDINGS: No differences were found between the recovered and depressed groups with respect to CRF test. Lower ACTH and higher cortisol levels with significant differences were shown in the neuroendocrine variables at 15, 30, and 60 min, and in peak response and increase, in the ACTH and cortisol response curves to CRF challenge between the groups of melancholic patients, both recovered and depressed, compared with the healthy control subjects. Moreover, recovered and depressed melancholic patients had a higher whole cortisol area under the curve with significant differences than the healthy control subjects. CONCLUSIONS: The crossover clinical status at the moment of the CRF test doesn't differentiate changes in the HPA axis in melancholic patients, while we did find significant differences in the group of healthy controls in comparison with the groups of melancholic patients both in depressive state and recovery. This supports the hypothesis that hypothalamic pituitary adrenal (HPA) axis shows alterations that remain in depressive patients even after recovery.