Plasma Adrenocorticotropin Hormone Levels Research Articles

Cadmium chronotoxicity at pituitary level: effects on plasma ACTH, GH, and TSH daily pattern

Cadmium is an endocrine disruptor that has been shown to induce chronotoxic effects. The present study was designed to evaluate the possible cadmium effects on the daily secretory pattern of adrenocorticotropin hormone (ACTH), growth hormone (GH), and thyroid-stimulating hormone (TSH) in adult male Sprague-Dawley rats. For this purpose, animals were treated with cadmium at two different doses [25 and 50 mg/l cadmium chloride (CdCl(2))] in the drinking water for 30 days. Control age-matched rats received cadmium-free water. After the treatment, rats were killed at six different time intervals throughout a 24-h cycle. Cadmium exposure modified the 24-h pattern of plasma ACTH and GH levels, as the peak of ACTH content between 12:00 and 16:00 h in controls appeared at 12:00 h in the group treated with the lowest dose used, while it appeared between 16:00 and 20:00 h in rats exposed to 50 mg/l CdCl(2). In addition, the peak of GH content found at 04:00 h in controls moved to 16:00 h in rats exposed to 25 mg/l CdCl(2), and the highest dose used abolished 24-h changes of GH secretion. The metal treatment did not modify ACTH secretory pattern. Exposure to cadmium also increased ACTH and TSH medium levels around the clock with both doses used. These results suggest that cadmium modifies ACTH and TSH medium levels around the clock, as well as disrupted ACTH and GH secretory pattern, thus confirming the metal chronotoxicity at pituitary level.

The role of the arginine vasopressin Avp1b receptor in the acute neuroendocrine action of antidepressants

In times of stress the hypothalamic-pituitary-adrenal (HPA) axis is activated and releases two neurohormones, corticotropin-releasing hormone (Crh) and arginine vasopressin (Avp), to synergistically stimulate the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary, culminating in a rise in circulating glucocorticoids. Avp mediates its actions at the Avp V1b receptor (Avpr1b) present on pituitary corticotropes. Dysregulation of the stress response is associated with the pathophysiology of depression and a major treatment involves increasing the availability of monamines at the synaptic cleft. Acute administration of selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) has previously been shown to activate the HPA axis. The present study was undertaken to evaluate the involvement of the Avpr1b in the HPA axis response to acute SC administration of an SSRI (fluoxetine 10mg/kg) and a TCA (desipramine 10mg/kg). We measured plasma ACTH and corticosterone (CORT) levels and neuropeptide mRNA expression in the hypothalamic paraventricular nucleus (PVN) of Avpr1b knockout (KO) mice and wild-type controls. Fluoxetine and desipramine administration significantly attenuated plasma ACTH and CORT levels in male and female Avpr1b KO mice when compared to their wild-type counterparts. Avp, oxytocin (Oxt) and Crh mRNA expression in the PVN did not change in fluoxetine-treated male Avpr1b KO or wild-type mice. In contrast, fluoxetine treatment increased PVN Avp mRNA levels in female Avpr1b wild type but not KO animals. PVN Oxt mRNA levels increased in fluoxetine-treated female mice of both genotypes. The data suggests that the Avpr1b is required to drive the HPA axis response to acute antidepressant treatment and provides further evidence of a sexual dichotomy in the regulation of PVN Avp/Oxt gene expression following antidepressant administration.

Relationship Between Plasma Adrenocorticotropin Hormone and Intensive Care Unit Survival in Early Traumatic Brain Injury

Hypothalamic pituitary adrenal response has been recently evaluated in patients with traumatic brain injury (TBI) with different results. Our objective was to study this response and its relationship with outcome in the early stage after TBI. We conducted a prospective observational clinical study in the intensive care unit of a tertiary level university hospital. The study included 50 consecutive patients who suffered isolated TBI. Intracranial pressure (ICP) was measured by an intraparenchymal probe. All patients were sedated and mechanically ventilated. Second-level measures were provided as per protocol, when needed. We measured plasma adrenocorticotropin hormone (ACTH) levels, as well as baseline and stimulated serum cortisol after a high-dose corticotrophin stimulation test, within 2 days after TBI for all patients. Mean age was 36 +/- 18 (range 16-77) years. Forty-four (88%) were male. Median Glasgow Coma Scale score was 7. Mean ACTH was 15.4 +/- 19.8 pg/mL. Mean baseline cortisol was 14.8 +/- 9.0 microg/dL and mean stimulated cortisol was 27.1 +/- 7.3 microg/dL and 30.5 +/- 7.2 microg/dL at 30 and 60 minutes, respectively. Baseline and stimulated cortisol were not correlated with mortality. Logistic regression analysis revealed that, either plasma ACTH levels <9 pg/mL or lack of indication to provide second-level measures to control ICP were significant independent predictors of survival. The presence of a low plasma ACTH concentration at an early stage of TBI and lack of indication to provide second-level measures to control ICP were associated with a higher intensive care unit survival.

CLINICAL AND IMAGING STUDY: Glucocorticoid negative feedback in methadone‐maintained former heroin addicts with ongoing cocaine dependence: dose–response to dexamethasone suppression

Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin-addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone-maintained former heroin addicts with ongoing cocaine dependence (C-MM), 10 stabilized methadone-maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C-MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C-MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C-MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C-MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long-term treatment with methadone.

A detailed characterization of loud noise stress: Intensity analysis of hypothalamo–pituitary–adrenocortical axis and brain activation

The present studies were undertaken to help determine the putative neural circuits mediating activation of the hypothalamo–pituitary–adrenocortical (HPA) axis and the release of adrenocorticotropin hormone (ACTH) and corticosterone in response to the perceived threat of loud noise. This experiment involved placing rats in acoustic chambers overnight to avoid any handling and context changes prior to noise exposure, which was done for 30 min (between 9:00 and 10:00 am) at intensities of 80, 85, 90, 95, 100, 105, and 110 dBA in different groups ( n = 8), and included a background condition (60 dBA ambient noise). This manipulation produced a noise-intensity-related increase in plasma ACTH and corticosterone levels, with levels beginning to rise at approximately 85 dBA. c- fos mRNA induction was very low in the brains of the control and 80 dBA groups, but several brain regions displayed a noise-intensity-related induction. Of these, several forebrain regions displayed c- fos mRNA induction highly correlated ( r > 0.70) with that observed in the paraventricular hypothalamic nucleus and plasma ACTH levels. These regions included the ventrolateral septum, the anteroventral subiculum, several preoptic nuclei, the anterior bed nucleus of the stria terminalis (BNST), the anterior paraventricular nucleus of the thalamus, and the medial subdivision of the medial geniculate body. Together with prior findings with audiogenic stress, the present results suggest that either or both the anterior BNST or the lateral septum is ideally situated to trigger HPA axis activation by stimuli that are potentially threatening.

Effects of Low- and High-Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men

The acute effects of smoking a low- or high-nicotine cigarette on hypothalamic-pituitary-adrenal (HPA) hormones, subjective responses, and cardiovascular measures were studied in 20 healthy men who met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for nicotine dependence. Within four puffs (or 2 min) after cigarette smoking began, plasma nicotine levels and heart rate increased significantly (P<0.01), and peak ratings of 'high' and 'rush' on a Visual Analogue Scale were reported. Reports of 'high', 'rush', and 'liking' and reduction of 'craving' were significantly greater after smoking a high-nicotine cigarette than a low-nicotine cigarette (P<0.05). Peak plasma nicotine levels after high-nicotine cigarette smoking (23.9+/-2.6 ng/ml) were significantly greater than after low-nicotine cigarette smoking (3.63+/-0.59 ng/ml) (P<0.001). After smoking a low-nicotine cigarette, adrenocorticotropin hormone (ACTH), cortisol, dehydroepiandrosterone (DHEA), and epinephrine did not change significantly from baseline. After high-nicotine cigarette smoking began, plasma ACTH levels increased significantly above baseline within 12 min and reached peak levels of 21.88+/-5.34 pmol/l within 20 min. ACTH increases were significantly correlated with increases in plasma nicotine (r=0.85; P<0.0001), DHEA (r=0.66; P=0.002), and epinephrine (r=0.86; P<0.0001). Cortisol and DHEA increased significantly within 20 min (P<0.05) and reached peak levels of 424+/-48 and 21.13+/-2.55 ng/ml within 60 and 30 min, respectively. Thus cigarette smoking produced nicotine dose-related effects on HPA hormones and subjective and cardiovascular measures. These data suggest that activation of the HPA axis may contribute to the abuse-related effects of cigarette smoking.

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization.

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.

Stress Hormone Dysregulation at Rest and After Serotonergic Stimulation Among Alcohol‐Dependent Men With Extended Abstinence and Controls

Alcohol dependence has been associated with long-lasting alterations in limbic-hypothalamic-pituitary-adrenal (LHPA) axis and serotonin (5-hydroxytryptamine [5-HT]) function. Other conditions that are associated with alcoholism (cigarette smoking and antisocial personality disorder [ASPD]) have been linked with disturbances in these interrelated systems. We evaluated the stress hormone response to 5-HTergic stimulation in alcohol-dependent men with extended abstinence (average abstinence duration, 4.3 months) and controls to determine the relative contributions of alcoholism, cigarette smoking, and ASPD on baseline and provoked plasma cortisol and adrenocorticotropin hormone (ACTH) concentrations. One hundred nine alcohol-abstinent men with alcohol dependence (62%), habitual smoking (70%), and ASPD (43%) received D,L-fenfluramine (100 mg po) in a randomized, double-blind, placebo-controlled, crossover trial. The group of recovering alcohol-dependent individuals included abstinent primary alcohol-dependent men and alcohol-dependent men with ASPD, whereas the group of non-alcohol-dependent men comprised healthy controls and non-alcohol-dependent men with ASPD. Plasma cortisol and ACTH levels were obtained at AM baseline and at half-hour intervals after drug administration. Subjective ratings of drug response and physiological measures were also obtained at baseline and every 30 min. Abstinent alcohol-dependent men had significantly lower (approximately 20%) AM baseline plasma cortisol concentrations than non-alcohol-dependent men on both challenge days; however, no differences between the groups were observed with regard to resting AM plasma ACTH levels. After adjusting for these baseline differences, recovering alcohol-dependent men (area under curve = 35.6 +/- 37.4 [microg/dl] x min) had a twofold greater cortisol response to fenfluramine than non-alcohol-dependent men (area under curve = 17.5 +/- 32.5 [microg/dl] x min) (F = 5.1; df = 1,105; p < 0.03). The elevated cortisol response, which occurred primarily along the descending limb of the response curve, was paralleled by a nonsignificant statistical trend for alcohol-dependent men to also exhibit a greater ACTH response to fenfluramine at the 210-min (p < 0.07) and 240-min (P < 0.09) time points as compared with non-alcohol-dependent men. Cigarette smoking and ASPD did not affect hormonal responses, nor could the groups' subjective ratings and physiological measures be distinguished. Alcohol-dependent men with extended abstinence differed from age- and race-matched non-alcohol-dependent men in resting AM and fenfluramine-induced plasma cortisol levels. This dysfunction in glucocorticoid homeostatic mechanisms was associated with alcoholism and not with smoking or ASPD. We also observed a nonsignificant statistical trend for plasma ACTH levels to be elevated among alcohol-dependent men along the descending limb of the response curve. Alcohol-dependent men seemed to have inherited or acquired damage to 5-HT-regulated LHPA axis function, the precise mechanisms and sites of which remain to be determined.

Stress Hormone Dysregulation at Rest and After Serotonergic Stimulation Among Alcohol-Dependent Men With Extended Abstinence and Controls

Background: Alcohol dependence has been associated with long-lasting alterations in limbic-hypothalamic-pituitary-adrenal (LHPA) axis and serotonin (5-hydroxytryptamine [5-HT]) function. Other conditions that are associated with alcoholism (cigarette smoking and antisocial personality disorder [ASPD]) have been linked with disturbances in these interrelated systems. We evaluated the stress hormone response to 5-HTergic stimulation in alcohol-dependent men with extended abstinence (average abstinence duration, 4.3 months) and controls to determine the relative contributions of alcoholism, cigarette smoking, and ASPD on baseline and provoked plasma cortisol and adrenocorticotropin hormone (ACTH) concentrations. Methods: One hundred nine alcohol-abstinent men with alcohol dependence (62%), habitual smoking (70%), and ASPD (43%) received d,l-fenfluramine (100 mg po) in a randomized, double-blind, placebo-controlled, crossover trial. The group of recovering alcohol-dependent individuals included abstinent primary alcohol-dependent men and alcohol-dependent men with ASPD, whereas the group of non-alcohol-dependent men comprised healthy controls and non-alcohol-dependent men with ASPD. Plasma cortisol and ACTH levels were obtained at AM baseline and at half-hour intervals after drug administration. Subjective ratings of drug response and physiological measures were also obtained at baseline and every 30 min. Results: Abstinent alcohol-dependent men had significantly lower (approximately 20%) AM baseline plasma cortisol concentrations than non-alcohol-dependent men on both challenge days; however, no differences between the groups were observed with regard to resting AM plasma ACTH levels. After adjusting for these baseline differences, recovering alcohol-dependent men (area under curve = 35.6 ± 37.4 [μg/dl] × min) had a twofold greater cortisol response to fenfluramine than non-alcohol-dependent men (area under curve = 17.5 ± 32.5 [μg/dl] × min) (F= 5.1;df= 1,105;p < 0.03). The elevated cortisol response, which occurred primarily along the descending limb of the response curve, was paralleled by a nonsignificant statistical trend for alcohol-dependent men to also exhibit a greater ACTH response to fenfluramine at the 210-min (p < 0.07) and 240-min (p < 0.09) time points as compared with non-alcohol-dependent men. Cigarette smoking and ASPD did not affect hormonal responses, nor could the groups’ subjective ratings and physiological measures be distinguished. Conclusions: Alcohol-dependent men with extended abstinence differed from age- and race-matched non-alcohol-dependent men in resting AM and fenfluramine-induced plasma cortisol levels. This dysfunction in glucocorticoid homeostatic mechanisms was associated with alcoholism and not with smoking or ASPD. We also observed a nonsignificant statistical trend for plasma ACTH levels to be elevated among alcohol-dependent men along the descending limb of the response curve. Alcohol-dependent men seemed to have inherited or acquired damage to 5-HT-regulated LHPA axis function, the precise mechanisms and sites of which remain to be determined.

Nitric Oxide Stimulates ACTH Secretion and the Transcription of the Genes Encoding for NGFI-B, Corticotropin-Releasing Factor, Corticotropin-Releasing Factor Receptor Type 1, and Vasopressin in the Hypothalamus of the Intact Rat

We investigated the effect of the intracerebroventricular injection of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) on the release of adrenocorticotropin hormone (ACTH) and the neuronal response of hypothalamic neurons responsible for this release. Rats that were administered SIN-1 showed significant elevations in plasma ACTH levels, a response that was virtually abolished by antibodies against corticotropin-releasing factor (CRF) and significantly blunted by vasopressin (VP) antiserum. SIN-1 also upregulated heteronuclear (hn) transcripts for CRF and VP and messenger RNA (mRNA) levels for the immediate early gene NGFI-B and for CRF receptor type 1 (CRF-R(1)) in the parvocellular portion of the paraventricular nucleus (PVN) of the hypothalamus. Blockade of prostaglandin synthesis with ibuprofen did not alter the ACTH or the PVN response to SIN-1. The central nucleus of the amygdala and the supraoptic nucleus, regions that are involved in autonomic adjustments to altered cardiovascular activity, also responded to SIN-1 with elevated NGFI-B mRNA levels. However, the only change in mean arterial blood pressure caused by this NO donor was a transient and modest increase. To our knowledge, this is the first demonstration that in the intact rat NO stimulates the activity of PVN neurons that control the hypothalamic-pituitary-adrenal axis. It must be noted, however, that our results do not allow us to determine whether this effect was direct or mediated through PVN afferents. This study should help resolve the controversy generated by the use of isolated brain tissues to investigate the net effect of NO on hypothalamic peptide production.

Gestational Cocaine Exposure Alters Postnatal Pituitary-Adrenal Axis Activity and Stress Endurance in Ratsa.

Female pregnant Sprague-Dawley rats were injected once daily with 40 mg/kg cocaine hydrochloride or 0.9% saline from gestational day 12 (GD 12) to GD 21. From postnatal day 21 (PND 21) to PND 60, both male and female offspring were examined for stress response. Treated male and female offspring demonstrated a diminished tolerance to stress as determined by a cold water stress test performed at PND 21, 30 and 40. Base hormonal levels of adrenocorticotropin hormone (ACTH) and corticosterone were not affected by prenatal cocaine exposure in male offspring at PND 30. However, immobilization for 1 hr caused a significant sustained elevation of corticosterone levels at both PND 30 and PND 60 in male treated offspring as compared to the control group. Plasma ACTH levels were also significantly sustained after 1 hr of immobilization at PND 60 for the cocaine-treated male offspring. These results indicate both a diminished capacity to respond to stress and an abnormal heightened reactivity of the pituitary-adrenal axis in offspring exposed to cocaine in utero.

Antidepressants Restore Hypothalamic-Pituitary-Adrenal Feedback Function in Aged, Cognitively-Impaired Rats

Aged, cognitively-impaired rats (and humans) show hypothalamic-pituitary-adrenal (HPA) hyperactivity that correlates with hippocampal damage. The resultant increase in plasma glucocorticoid exposure is thought to contribute to impaired hippocampal function and to potentiate hippocampal neuron death. In young, adult rats antidepressant drugs increase corticosteroid receptor expression in brain regions known to regulate the HPA axis, leading to increased negative-feedback control and decreased HPA activity. In the present study we examined basal levels of plasma adrenocorticotropin hormone (ACTH) and corticosterone in aged, cognitively-impaired (AI), aged, cognitively-unimpaired (AU) and young, adult (Yg) rats. Plasma ACTH and corticosterone levels were significantly elevated in the AI rats, but only in samples obtained during the diurnal peak. Five weeks of treatment with desipramine (15 mg/kg) significantly reduced evening levels of both ACTH and corticosterone in all groups, and eliminated the group differences. We then examined delayed, glucocorticoid negative feedback in these animals. Among vehicle-treated animals, a bolus injection of corticosterone (10 mg/kg), administered 3 hours prior to testing, completely inhibited the plasma ACTH response to restraint in AU and Yg, but not AI animals. In contrast, plasma ACTH responses to restraint were completely inhibited in AI rats following chronic treatment with desipramine. These findings indicate that the antidepressant, desipramine, decreases HPA activity and increases glucocorticoid negative-feedback sensitivity in AI rats, suggesting that antidepressant drugs may form a useful therapeutic approach to HPA dysfunction in elderly human populations.

Central administration of the neurotensin receptor antagonist, SR48692, modulates diurnal and stress-related hypothalamic-pituitary-adrenal activity.

Previous studies in our laboratory suggest that neurotensin (NT) acts centrally to modulate adrenocorticotropin hormone (ACTH) and corticosterone release. In the present studies, we examined hypothalamic-pituitary-adrenal (HPA) function under basal conditions and during restraint stress following central administration of the highly specific NT receptor antagonist, SR48692. Chronic delivery of SR48692 to the paraventricular nucleus (PVN) of the hypothalamus via indwelling central cannulae attenuated both the diurnal- and stress-induced elevations in HPA activity. Thus, SR48692 decreased the diurnal increase in plasma ACTH and corticosterone during the evening phase of the cycle, but did not affect morning levels. Restraint-induced increases in plasma ACTH and corticosterone levels were also significantly reduced in the SR48692-implanted animals. This suggests that the inhibitory effects of SR48692 were restricted to periods of stimulated HPA activity. A decrease in corticotropin-releasing hormone (CRH)-like immunoreactivity was observed within the PVN following chronic SR48692, and parallel decreases in CRH-like immunoreactivity were observed within the external zone of the median eminence. These findings suggest that endogenous NT serves to increase HPA activity during periods of enhanced stimulation.

Adrenaline release by the 5-HT 1A receptor agonist 8-OH-DPAT is partly responsible for pituitary activation

In male Wistar rats the effect of adrenalectomy on pituitary activation by the 5-HT 1A receptor agonist, 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), was studied. Rats were injected intravenously with 8-OH-DPAT (0.10 mg/kg) in their home cages. Blood samples were withdrawn from freely moving cannulated rats for determination of plasma adrenaline and plasma adrenocorticotropin hormone (ACTH). Adrenalectomized rats showed almost no measurable amounts of plasma adrenaline, but these animals had elevated baseline plasma ACTH levels as compared to sham-operated rats. 8-OH-DPAT treatment led to a large plasma adrenaline response in the sham-operated animals, which was abolished after adrenalectomy. The plasma ACTH response to 8-OH-DPAT was significantly diminished in the adrenalectomized rats as compared to sham animals. This blunted ACTH response in adrenalectomized rats, however, was still considerable in magnitude. The present data thus indicate that the plasma ACTH response to 8-OH-DPAT is due to at least two different mechanisms. First, via 5-HT 1A receptor-mediated adrenaline release, which may consequently stimulate the pituitary. Second, a direct action of 8-OH-DPAT on hypothalamic 5-HT 1A receptors is assumed, independent of peripheral adrenaline release.

Differential development of the stress response in congenital learned helplessness

Early in the development of the hypothalamic-pituitary-adrenal (HPA) axis, the rat undergoes a stress hyporesponsive period of blunted responses to several Stressors including cold exposure (CE) and maternal deprivation (MD). We examined the development of the axis by monitoring adrenocorticotropin hormone (ACTH) plasma levels in an animal model of depression and/or anxiety characterized by learned helpless (LH) behavior and a dysfunctional HPA axis in adult life. On postnatal day 7 there was no significant difference in basal plasma ACTH levels between congenital (cLH) and controls, but cLH animals showed a blunted response to CE (P<0.001). By postnatal day 14 there was a dramatic increase in ACTH response to CE (P<0.005). On postnatal day 21 baseline ACTH and response to CE were again significantly suppressed in cLH rats. Stress responsiveness to MD was present in all groups and was insignificantly different for all ages of development between groups. These findings suggest that rats with congenital learned helplessness undergo a differential response in the development of the HPA axis in that the axis was hypersensitive at postnatal day 14 and became hyporesponsive beyond day 14 and this may, in part, account for the dysfunctional stress response observed during adulthood.

Effects of alprazolam on pituitary-adrenal and catecholaminergic responses to metabolic stress in humans

Concurrent effects of benzodiazepines on stress-induced activation of the three classical “stress” systems: pituitary-adrenal, adrenomedullary, and sympathoneural systems have not been extensively investigated in humans. In the present study, the effects of alprazolam (1.5 mg) on plasma levels of adrenocorticotropin hormone (ACTH), epinephrine, norepinephrine, dihydroxyphenylglycol (DHPG, the intraneuronal metabolite of norepinephrine), and mood states were examined in 10 healthy volunteers undergoing glucoprivic stress. Glucoprivic stress was induced by intravenous administration of the glucose analog, 2-deoxyglucose (2DG), at a dose (50 mg/kg) that impairs cellular glucose metabolism and produces a state comparable to hypoglycemia. Alprazolam and 2DG were administered in a double-blind, placebo-controlled manner. 2DG produced robust elevations in plasma ACTH and epinephrine levels, modest elevations in plasma norepinephrine levels, and decreases in plasma DHPG levels. Alprazolam significantly attenuated the 2DG-induced increases in plasma ACTH and epinephrine, but did not significantly effect plasma norepinephrine and DHPG. These data suggest that benzodiazepines attenuate metabolic stress-induced activation of the pituitary-adrenal and adrenomedullary systems but do not effect 2DG-related effects on peripheral sympathoneural function. The possible mechanisms involved are discussed.

Chapter 27 Peptidergic transmitters of the suprachiasmatic nuclei and the control of circadian rhythmicity

Publisher Summary This chapter describes peptidergic transmitters of the suprachiasmatic nuclei and the control of circadian rhythmicity and the plasma corticosterone rhythm, because corticotropin-releasing factor (CRF) neurons, regulating the release of adrenocorticotropin hormone (ACTH) and corticosterone, are located in the paraventricular nucleus (PVN). The close relationship between the changes in plasma ACTH and corticosterone levels indicates that the inhibitory effect of vasopressin (VP) involves the hypothalamo-pituitary pathway. Together with the data on the circadian rhythmicity of VP levels in the cerebrospinal fluid (CSF), which are inversely related to the rhythm of plasma corticosterone, the results show how the suprachiasmatic nucleus (SCN) might be able to induce the circadian fluctuations in the plasma levels of this important steroid hormone. The chapter proposes a hypothesis that VP released from the SCN projections may serve to inhibit arousal during the inactive part of an animal's sleep/waking cycle. However, studies involving other transmitters of the SCN may provide further insight in how this small nucleus in the basal hypothalamus is able to modulate such a variety of physiologically important functions.

Beta-endorphin, ACTH, and cortisol response to hemorrhage in conscious pigs.

Some of the interrelations of neuroendocrine changes associated with hypovolemia were investigated in a model simulating an arterial hemorrhage. beta-Endorphin, adrenocorticotropin hormone (ACTH), and cortisol levels were measured by radioimmunoassay before, during, and after controlled bleeding of conscious splenectomized pigs. All animals showed significant (P less than 0.05) increases in the three neuroendocrine substances during hemorrhage. beta-Endorphin values initially were 55 +/- 7 pg/ml (+/- SE) and rose to a peak of 386 +/- 44 pg/ml at the nadir of blood pressure (mean arterial pressure = 47.5 mmHg). ACTH showed a similar pattern, increasing from 49 +/- 10 to a peak of 518 +/- 56 pg/ml. Cortisol values reached their peak of 18.2 +/- 2.5 micrograms % during the recovery phase. beta-Endorphin values displayed a close inverse correlation to blood pressure during hemorrhage, but returned to basal levels more rapidly than blood pressure during the recovery period. Plasma ACTH levels rose significantly more slowly than beta-endorphin as the hemorrhage progressed. An equimolar ratio of ACTH and beta-endorphin returned only as levels declined following the hemorrhagic insult. In awake pigs therefore an arterial hemorrhage is accompanied by endorphin release proportional to the decrement in blood pressure, a somewhat retarded buildup of ACTH, and a still later cortisol peak during recovery.

Responses of ACTH, epinephrine, norepinephrine, and cardiovascular system to hemorrhage.

Hemorrhages of various magnitudes were performed on conscious rats, and arterial pressure, heart rate, and plasma levels of adrenocorticotropin hormone (ACTH), epinephrine, and norepinephrine were measured. Eight rats were prepared with chronic femoral arterial cannulas and received a 10, 15, or 20 ml/kg X 3 min hemorrhage in random order on day 4, 7, or 10 after surgery. Mean arterial blood pressure, heart rate, and plasma ACTH, epinephrine, and norepinephrine concentrations were determined before and 20 min after hemorrhage. Arterial blood pressure decreased significantly immediately after each hemorrhage and slowly recovered over the next 20 min. Heart rate did not change during the 10 ml/kg X 3 min hemorrhage but decreased significantly after 15 and 20 ml/kg X 3 min hemorrhages. Plasma ACTH and epinephrine levels increased significantly 20 min after the 15 and 20 ml/kg X 3 min hemorrhages but not after 10 ml/kg X 3 min hemorrhage. Norepinephrine increased significantly 20 min after the 20 ml/kg X 3 min hemorrhage but not after the 10 or 15 ml/kg X 3 min hemorrhage. There was no significant effect of time and repeated hemorrhages on resting levels of plasma ACTH, epinephrine, norepinephrine, osmolality, or proteins. Since hemorrhage leads to a fall in arterial pressure and a subsequent rise in plasma ACTH, the relationship between plasma ACTH and mean arterial blood pressure during hemorrhage was examined in both conscious and acutely prepared pentobarbital sodium-anesthetized rats.(ABSTRACT TRUNCATED AT 250 WORDS)