Corticosterone Release In Response Research Articles

Long-lasting, sex- and age-specific effects of social stressors on corticosterone responses to restraint and on locomotor responses to psychostimulants in rats

Many neural systems are undergoing marked development over adolescence, which may heighten an animal's vulnerability to stressors. One consequence may be altered sensitivity to drugs of abuse. We previously reported that social stressors in adolescence increased behavioral sensitization to nicotine in adulthood in female, but not male, rats. Here we examined whether social stressors in adolescence alter the functioning of the hypothalamic–pituitary–adrenal (HPA) axis by examining corticosterone release in response to restraint in adulthood. To further assess effects of social stressors on behavioral sensitivity to psychostimulants, we examined locomotor activity in response to nicotine and to amphetamine. In a second set of experiments, we investigated whether the same procedure of social stressors administered in adulthood produces effects similar to that observed when administered in adolescence. Rats underwent daily 1 h isolation followed by pairing with a new cage mate on either postnatal days 33–48 (pubertal stress: PS) or days 65–80 (adult stress: AS). Three weeks later rats tested for either: (a) corticosterone levels were measured in response to restraint, or (b) locomotor sensitization to nicotine (0.25 mg/kg; 5 days) followed by an amphetamine challenge (0.5 mg/kg) 24 h later. Effects of social stressors were evident only in females. PS females had increased locomotor activity to amphetamine compared to controls, and AS females had increased corticosterone release compared to controls. No effect of the social stressors was found in males at either age except for reduced weight gain during the stress procedure. Thus, females are more susceptible to the enduring effects of these moderate social stressors than are males. However, in terms of behavioral sensitivity to drugs of abuse, females may be more susceptible to stressors during adolescence than adulthood, although the reverse appears to be true for HPA function.

Corticosterone secretion induced by chronic isolation in neonatal rats is sexually dimorphic and accompanied by elevated ACTH

Rat pups repeatedly subjected to brief periods of isolation during the stress hyporesponsive period (SHRP) exhibit varied neuroendocrine and behavioral changes as neonates and as adults. For example, neonatal rats exhibit increased circulating corticosterone after 1-h isolation on postnatal day 9 (P9) only if they were isolated daily from P2 to P8 [McCormick, C.M., Kehoe, P., Kovacs, S., 1998. Corticosterone release in response to repeated, short episodes of neonatal isolation: evidence of sensitization. Int. J. Dev. Neurosci. 16, 175–185]. It is not known if the increase in adrenocortical response on P9 following repeated isolation is mediated by increased pituitary ACTH secretion. The present study examined the responsivity of the hypothalamic–pituitary–adrenal (HPA) axis during the SHRP following brief, repeated isolation or acute pharmacological manipulation. Removal from the nest for 1 h daily on P4–8 increased circulating corticosterone after 1-h isolation on P9 by approximately twofold. Neither unhandled nor handled controls showed a corticosterone response to 1-h isolation on P9. The increased corticosterone was sexually dimorphic, with only females showing the sensitization response. Other findings suggest that the hormonal response is centrally mediated; chronically isolated pups of both sexes exhibit increased plasma ACTH following 1-h isolation on P9. While we could not detect an increase in Fos immunoreactivity (IR) on P9 in the hypothalamic paraventricular nucleus (PVN) of chronically isolated pups, acute pharmacological activation of serotonin 2A/2C receptors produced robust activation of ACTH and corticosterone secretion as well as expression of Fos in the PVN on P9. We conclude that chronic isolation stress limited to the SHRP stimulates the neonatal HPA axis, and that the adrenal response is sexually dimorphic. In addition, PVN neurons can express Fos IR on P9 in response to a very potent activation of the HPA axis.

Different activation of ACTH and corticosterone release in response to various stressors in rats.

The aim of this study was to investigate the reaction of the hypothalamo-pituitary-adrenocortical (HPA) system to various stressors (fasting, crowding, cold and heat) by measuring blood ACTH and corticosterone (CORT) concentration as well as the cholesterol (CHOL) content in the adrenals. To examine the effects of stress termination, the rats were returned and kept under control conditions for the same period as that of stress duration (supposed recovery period). According to our results HPA system was activated by all the stressors applied. Heat seems to be the strongest stressor since the exposure of animals to a high ambient temperature resulted in the greatest rise of plasma ACTH concentration as well as CORT synthesis and secretion. These values remained elevated after the stress termination i.e. after the rats had been returned to room temperature. Fasting seems to be the weakest stressor given because it causes the smallest increase in blood ACTH and CORT concentrations. Moreover, in refed rats the HPA function was fully recovered. In conclusion, the various stressors applied seem to induce a different response of the HPA system as judged by quantitative changes in ACTH and CORT release.

Shared genes influence sensitivity to the effects of ethanol on locomotor and anxiety-like behaviors, and the stress axis.

In rodents, a common response to many drugs of abuse, including ethanol (EtOH), is locomotor stimulation. It has been proposed, although debated, that EtOH-induced locomotor stimulation may represent an animal model of EtOH's euphoric effects. Another possibility is that this behavioral phenotype may represent an altered state of anxiety, and/or stress axis activation. Mouse lines selectively bred for sensitivity (FAST) or resistance (SLOW) to EtOH's low dose locomotor stimulant effects were tested for differential sensitivity to EtOH's anxiolytic and/or stress axis activating effects, with the goal of detecting genetic correlations. Saline- and EtOH-treated FAST and SLOW mice were tested on the elevated plus maze and the light-dark box, two widely used measures of anxiety-related behavior in rodents. In addition, serum corticosterone (CORT) levels were measured at various time points following injection of saline or ethanol. Behavioral data from both anxiety tests showed that FAST mice were less sensitive to EtOH's anxiolytic effects than were SLOW mice. Moreover, late recovery of elevated serum CORT levels following mild saline injection stress, as well as reduced CORT release in response to EtOH, suggested that FAST mice may possess a less responsive stress axis. These results provide evidence that sensitivity to the effects of EtOH on locomotor behavior, anxiety-like behavior, and the stress axis share some genetic influence.

Effects of neonatal corticosterone treatment on maze performance and HPA axis in juvenile rats

Previous research has indicated that administering corticosterone to dams' drinking water for 21 days produced persistent alterations in physiology and behavior. We investigated whether 4 days of corticosterone exposure would have similar effects, and whether greater effects would be found when corticosterone was administered early in neonatal life than later in neonatal life. Sprague–Dawley dams were given either corticosterone (250 μg/ml) in their water bottles for postnatal days (PND) 5–9 (early corticosterone treatment: ECT), PND 13–17 (late corticosterone treatment: LCT) or no treatment (NT). At the end of treatment, corticosterone levels were higher in pups of corticosterone drinking dams. However, at weaning, ECT and LCT pups had lower basal corticosterone levels than NT pups. As juveniles, ECT pups learned to navigate to a visible and then to a nonvisible platform in a Morris water maze more quickly than did LCT and NT pups. Among females, ECT pups had higher corticosterone release in response to stress than LCT and NT pups. There were no differences in hippocampal corticosteroid receptor levels among the groups. The pattern of results is similar to, but not identical to, that found for pups exposed to corticosterone for 21 days. The results also suggest that there is a critical or sensitive period for corticosterone treatment in that early treatment was more effective than later treatment.

Corticosterone release in response to repeated, short episodes of neonatal isolation : evidence of sensitization

Repeated isolation of neonatal rats produces persistent changes in physiology and behavior. In Experiment 1, we examined changes in plasma corticosterone (CORT) levels as a possible mechanism for the effects of isolation. Pups that were isolated from their mother and the nest for 1 h per day on postnatal days (PND) 2–9 were compared to control litters of pups that were either nonhandled or handled but not isolated. On PND 2, compared to nonhandled pups, handled pups had elevated CORT levels that returned to baseline levels within 30 to 60 min of return to the home cage. No significant elevation of CORT levels were found in handled pups on PND 9. The CORT levels of isolated pups were over twice those of nonhandled pups on PND 2 and four times those of nonhandled pups on PND 9. In Experiment 2, we investigated whether the increased CORT release in response to isolation on PND 9 was the result of the pups treatment on the previous six days as against an effect of maturation. Plasma CORT levels were measured in rat pups that were either isolated, handled or nonhandled on PNDs 2–8 during the conditions of isolation, handling and nonhandling on PND 9. There were no differences among the groups in basal plasma levels of CORT. Handling on PND 9 did not result in elevated CORT levels in any of the groups. All three groups showed a significant increase in plasma CORT levels after isolation on PND 9. However, the CORT response to isolation of pups previously isolated on PND 2–8 were significantly higher than pups that were either handled or nonhandled on PNDs 2–8. Thus, daily episodes of isolation potentiate the hypothalamic-pituitary-adrenal response to stress.

The Hypothalamus and Adrenal Regulate Modulation of Corticosterone Release in Redpolls (Carduelis flammea—An Arctic-Breeding Song Bird)

Free-living redpolls (Carduelis flammea—a species that breeds in the Alaskan Arctic), modulate corticosterone release in response to capture and restraint depending upon the breeding site. We extended these findings to adults undergoing a prebasic molt (the energetically costly replacement of feathers) and to juveniles. Results indicate not only that the stress response is dramatically reduced at one breeding site, but that the stress response during molt and in juveniles is lower still. In fact, juveniles failed to secrete any corticosterone in response to capture and handling, suggesting a stress hyporesponsive period. We also examined possible mechanisms underlying stress modulation. Corticosterone binding protein capacity does not change, and the stress response is only correlated with the overall condition of the bird (assessed by fat storage) at one site, suggesting that neither can explain the different corticosterone responses. Adrenal insensitivity also does not appear to fully explain reduced maximal output since exogenous ACTH enhanced corticosterone release. Exogenous ACTH, however, cannot stimulate corticosterone to stress-induced levels at the high-response site, implying reduced adrenal capacity. Redpoll pituitaries responded to exogenous corticotrophin-releasing factor and arginine vasotocin, suggesting a mechanism upstream from the pituitary blunts corticosterone release. Taken together, these results indicate that corticosterone release in this species is modulated depending upon the ecological and physiological state of the animal, and that the maximal corticosterone response is controlled at multiple sites in the hypothalamic–pituitary–adrenal axis.

Lesions of the Medial Geniculate Nuclei Specifically Block Corticosterone Release and Induction of c-fosmRNA in the Forebrain Associated with Audiogenic Stress in Rats

Audiogenic stress is known to activate the hypothalamo-pituitary-adrenocortical (HPA) axis in rats. The goal of the present study was to determine whether the medial geniculate nuclei (including all auditory nuclei of the thalamus), which are obligatory relays in the transmission of auditory information to the forebrain, are critically involved in HPA activation by audiogenic stress. To this end, corticosterone levels and regional brain activity indexed by c-fos mRNA induction, elicited by 30 min of 105 dB white noise, were measured. Compared with unoperated and sham-operated rats, complete medial geniculate nuclei lesions blocked corticosterone release normally induced by loud noise. The effects of the lesions were specific to loud noise insofar as corticosterone release in response to restraint or ether stress was not reduced in lesioned rats. We have determined previously that audiogenic stress is associated with a specific regional pattern of c-fos mRNA induction. Rats sustaining complete medial geniculate lesions demonstrated a blockade of c-fos mRNA induction in several audiogenic stress responsive regions, also known to directly innervate medial parvocellular neurons of the paraventricular hypothalamic nucleus. Thus, in addition to blockade in the paraventricular hypothalamic nucleus, c-fos mRNA induction in the lesioned animals was abolished in the bed nucleus of the stria terminalis, especially its anterior medial and ventral aspects, the septohypothalamic nucleus, and the anteroventral preoptic area, compared with unoperated and sham-operated rats. Several additional regions in the lesioned rats failed to show reliable c-fos mRNA induction compared with naive rat controls. Nearly all other regions that showed reliable c-fos mRNA induction in the unoperated and sham-operated rats displayed either similar or slightly reduced levels in complete medial geniculate-lesioned rats, suggesting that these regions are not part of a critical HPA activational circuit in response to audiogenic stress. On the basis of these results, putative circuits from the medial geniculate nuclei to the paraventricular nucleus of the hypothalamus involved in activation of the HPA axis by audiogenic stress are discussed.

Time course of the effect of maternal deprivation on the hypothalamic‐pituitary‐adrenal axis in the infant rat

Prolonged (i.e., 24-hr) maternal deprivation leads to a marked disinhibition of the infant rat's adrenocortical response to stress and/or ACTH. In the following study we examined the time course over which these effects develop. Pups were maternally deprived for varying lengths of time (i.e., 0, 2, 4, 8, & 24 hr); at the end of this period, corticosterone (CORT) secretion in response to stress (novelty or novelty plus saline injection) and ACTH injection was measured. Basal levels of CORT increased progressively over time in 7- and 11- (but not 3-) day-old pups. CORT release in response to stress followed a similar pattern. In contrast, ACTH injection resulted in marked increases in CORT levels regardless of the length of maternal deprivation in 3-day-old animals; at older ages, however, 24 hr of deprivation led to a much larger increase. These findings support the hypothesis that the hypothalamic-pituitary-adrenal axis of the neonatal rat is subject to maternal regulation.

Studies on the mechanism of corticotrophin-mediated desensitization of corticosterone secretion by rat adrenocortical cells

Long-term exposure of the adrenocortical cells in vivo or in vitro to high concentrations of ACTH results in a diminution of the responsiveness of these cells to a subsequent stimulation of corticosterone release by ACTH. Conflicting studies have been published on the mechanism of this ‘desensitization’ phenomenon. Dispersed adrenocortical cells prepared from the hypertrophic/hyperplastic adrenal glands of rats bearing the ACTH/PRL-secreting rat pituitary tumour 7315a showed an increased basal release of corticosterone, but had lost their ability to respond further to ACTH. However, corticosterone release in response to dibutyryl cyclic AMP (dbcAMP), cholera toxin and forskolin remained intact. Pretreatment of normal rats for 3, 9 and 21 days with 50 μg/rat/day of a long-acting ACTH 1–24 depot preparation induced a dose-dependent increase in basal corticosterone release by the adrenocortical cells prepared from these animals and a dose-dependent decrease in the sensitivity to ACTH. However, the responsiveness of the adrenocortical cells prepared from the adrenal glands of control and ACTH 1–24 pretreatment rats to dbcAMP, cholera toxin and forskolin was similar. In addition, pretreatment with ACTH in vivo did not affect the sensitivity of the adrenocortical cells in vitro to calmodulin inhibition by haloperidol and 11β-hydroxylase inhibition by etomidate. It is concluded that long-term exposure of the adrenal gland to high concentrations of ACTH in vitro results in an excessive activation of corticosterone release by the adrenocortical cells in vitro, which is accompanied by a loss of sensitivity to ACTH. The sensitivity of these cells to cholera toxin and forskolin remains unchanged. The mechanism which might explain these phenomena includes down-regulation of the ACTH receptors or uncoupling of the ACTH receptor complex from the N s subunit.

Recovery of the hypothalamo-pituitary-adrenocortical axis in the rat after long-term dexamethasone treatment.

Male rats were treated for 14 days with dexamethasone (2.6 mumol/l in the drinking water) and killed at various times after withdrawal of the drug. Some animals were subjected to stress (ether or sham adrenalectomy) just before killing. The recovery of responsiveness of the components of the hypothalamo-pituitary-adrenocortical axis was assessed by measuring plasma and tissue concentrations of hormones, and the response of the tissue in vitro to appropriate stimuli. In vitro, bioactive corticotrophin-releasing factor (CRF) release in response to acetylcholine and adrenal corticosterone release in response to adrenocorticotrophin (ACTH) were significantly suppressed until 3 days after withdrawal. However, release of immunoreactive or bioactive ACTH in response to ovine CRF or hypothalamic extract did not return to normal until day 5. This was correlated with a reduction in pituitary immunoreactive ACTH content and bioactive plasma ACTH, which were suppressed until days 5 and 4, respectively. No change in hypothalamic immunoreactive CRF content could be detected after treatment, or after stress (ether or sham adrenalectomy) in either treated or control animals. Stress (ether) had no effect on the subsequent response of the anterior pituitary gland in vitro to ovine CRF. The large rises in plasma ACTH and adrenal corticosterone measured after stress (ether) in control animals were completely abolished after dexamethasone treatment and did not return to control values until 5 days after withdrawal. Therefore, it appears that after cessation of chronic dexamethasone treatment in the rat, the responsiveness of the hypothalamus and adrenal gland return to normal before that of the pituitary gland.

Interaction of Aging with <i>in vitro </i>Adrenocortical Responsiveness to ACTH and Cyclic AMP

In vitro adrenal accumulation of cyclic 3'5'-adenosine monophosphate (cyclic AMP) and release of corticosterone in response to adrenocorticotropic hormone (ACTH), cyclic AMP or theophylline was assessed in 60- and 340-day-old male rats. Adrenal tissue from mature animals secreted significantly smaller quantities of corticosterone in response to ACTH, theophylline or cyclic AMP. Additionally, mature tissue accumulated significantly less cyclic AMP after treatment with ACTH or a combination of ACTH and theophylline. The data suggest an age-related refractoriness of adrenal cortical tissue to ACTH which may in part be related to decreased availability of and/or sensitivity to cyclic AMP.

Dissociation of adrenal ascorbic acid and corticosterone responses to stress in rats with hypothalamic lesions.

A dichotomy has been observed between the adrenal ascorbic acid and corticosterone response to surgical stress in male rats with bilateral electrolytic lesions placed in the hypothalamus. Thus lesions in the posterior and midcentral portions of the hypothalamus specifically inhibited corticosterone release without altering adrenal ascorbic acid response or the weights of target organs dependent upon the normal production of pituitary hormones. Similarly, lesions in the basal tuberal region inhibited adrenal ascorbic acid depletion without affecting corticosterone release in response to stress. However, the latter lesions (which involved the median eminence) were not adrenal specific inasmuch as atrophy of the testes, seminal vesicles and prostate was also noted. Gross damage to the median eminence, basal tuberal region and portal systems blocked both adrenal responses and frequentty resulted in atrophy of the thyroid and adrenal glands as well as of the sexual target organs. Water intake following hypothalamic damage was not correlated with adrenal responsiveness. Possible explanations are discussed for the ability of the adrenal to exhibit discriminatory responses to stress following hypothalamic lesions.