Behavioral activity and stress reaction of the pituitary-adrenocortical axis in rat with prenatal inhibition of testosterone metabolism

The effects of maternal administration of the aromatase inhibitor, 1,4,6-androstatrien-3,17-dione (ATD), during the last week of gestation on stress reaction of the hypothalamic-pituitary-adrenal axis (HPA) and behavior in a novel environment (open field) and the anxiety level in the elevated plusmaze, were studied in male and female adult offspring. The results showed that parental inhibition of brain testosterone metabolism decreases the basic level of corticosterone in male rats and prolongs hormonal stress reaction of the HPA axis in both sexes. Prenatally treated rats demonstrated significant elevation of the anxiety level and emotionality. There was no sexual dimorphism in behavioral response to a novel environment such as locomotor activity, the time of immobilization, the total duration of grooming reaction, and the anxiety level, between control male and treated female rats. These data suggest a prenatal inhibition of the brain testosterone metabolism after the stress reaction of HPA axis and formation of sexual dimorphism in the anxiety and behavioral response to a novel environment in adulthood.     

Effects of maternal deprivation on adrenal and behavioural responses in rats with anterodorsal thalami nuclei lesions

There is evidence that repeated maternal isolation of neonatal rats may influence both emotional behavior and Hypothalamic-Pituitary Adrenal (HPA) activity. On the other hand the Anterodorsal Thalami Nuclei (ADTN) exerts an inhibitory influence on the hypophyso-adrenal system under basal and stressful conditions. In the present work we investigated whether neonatal maternal deprivation produces long term effects on the ADTN regulation of behavioral patterns (open field test) and on HPA axis activity. Specifically, we sought to determine whether adult female rats with ADTN lesions, previously isolated for 4.5 hours daily during the first 3 weeks of life, react in endocrinologically and behaviourally distinct manner as compared to controls. The examined groups were: non maternally deprived (NMD)/sham lesioned, NMD/lesioned, maternally deprived (MD)/sham lesioned, MD/lesioned with and without the open field test. At 3 months MD/sham lesioned animals showed a marked decrease in ambulation (P < 0.01), and with ADTN lesion, the rearing values were lower (P < 0.01) and grooming higher (P < 0.05) than NMD. This last data would indicate a high emotional index. Regarding the activity of the HPA axis, maternal deprivation induced a significant decrease in plasma ACTH concentration both in sham and lesioned animals (P < 0.001), and plasma Corticosterone (C) increased in sham animals (P < 0.001). This data would indicate a higher sensitivity of the adrenal glands. After the open field test ACTH and C were different between deprived and non-deprived animals depending on the ADTN lesion. Taking into consideration the increase of ACTH levels in sham lesioned MD animals exposed to the test, we could conclude that this new situation was a stressful situation. Finally in the present work, it was very difficult to relate the behavioral parameters with the endocrine data. It is known that depending on the context, corticosteroids may produce opposite effects on emotional behavior via different receptors in the brain.In summary, neonatal maternal deprivation induced alterations of behavioral patterns and affected the ADTN inhibitory influence on ACTH and C secretion.     

Intracerebroventricular ACTH activates the pituitary-adrenal system:dissociation from a behavioral response.

In the rat, intracerebroventricular injection of synthetic ACTH (ACTH_1–24, ACTH_1–16) elevated plasma corticosterone levels and induced the display of excessive grooming behavior. The grooming response could be elicited in hypophysectomized rats without concommittant elevation of plasma corticosterone. In intact rats subcutaneous injection of ACTH_1–24 and not of ACTH_1–16-NH₂ stimulated the release of adrenal corticosteroids, whereas no excessive grooming was observed. In contrast to the reduced effectiveness of a second icv injection of ACTH in inducing the behavioral response, no single-dose tolerance was observed for the effect of icv ACTH on the pituitary-adrenal system. Therefore it was concluded that two different central mechanisms underly the observed responses to the icv applied ACTH.     

Endocrine, behavioral and autonomic effects of neuropeptide AF

The actions of neuropeptide AF (NPAF), on the hypothalamic-pituitary-adrenal (HPA) axis, behavior and autonomic functions were investigated. NPAF (0.25, 0.5, 1, 2 nmol) was administered intracerebroventricularly to rats, the behavior of which was monitored by means of telemetry, open-field (OF) observations and elevated plus-maze (EPM) tests. The temperature and heart rate were recorded by telemetry, and the plasma ACTH and corticosterone levels were used as indices of the HPA activation. The dopamine release from striatal and amygdala slices after peptide treatment (100 nM and 1 μM) was measured with a superfusion apparatus. To establish the transmission of the HPA response, animals were pretreated with the corticotrophin-releasing hormone (CRH) receptor antagonist antalarmin or astressin 2B (0.5 nmol). In the OF test, the animals were pretreated with antalarmin or haloperidol (10 μg/kg), while in the EPM test they were pretreated with antalarmin or diazepam (1 mg/kg). NPAF stimulated ACTH and corticosterone release, which was inhibited by antalarmin. It activated exploratory locomotion (square crossings and rearings) and grooming in OF observations, and decreased the entries to and the time spent in the open arms during the EPM tests. The antagonists inhibited the locomotor responses, and also attenuated grooming and the EPM responses. NPAF also increased spontaneous locomotion, and tended to decrease the core temperature and the heart rate in telemetry, while it augmented the dopamine release from striatal and amygdala slices. These results demonstrate, that acute administration of exogenous NPAF stimulates the HPA axis and behavioral paradigms through CRH and dopamine release.     

The involvement of nitric oxide and prostaglandins in the cholinergic stimulation of hypothalamie-pituitary-adrenal response during crowding stress.

The aim of the present study was to determine the effect of social crowding stress and significance of nitric oxide (NO) and prostaglandins (PG) generated by constitutive and inducible nitric oxide synthase (NOS) and cyclooxygenase (COX) in the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by cholinergic muscarinic receptor agonist carbachol. Inhibitors of neuronal NOS (nNOS) L-NNA, general NOS L-NAME and inducible NOS (iNOS) aminoguanidine, as well as inhibitors of COX-1, piroxicam, and COX-2, compound NS-398 were administered 15 min prior to carbachol to control or crowded rats (24 rats in cage for 7, during 3 and 7 days). In stressed rats L-NAME, L-NNA and aminoguanidine significantly intensified the carbachol-induced ACTH and corticosterone secretion, like in control rats. Piroxicam, markedly decreased the carbachol-induced ACTH and corticosterone response under either basal or stress conditions. Compound NS-398 did not markedly alter the carbachol-induced HPA response in control and stressed rats. Crowding stress (3 days) significantly impaired the i.c.v. prostaglandin E(2)-induced ACTH response. Corticotropin releasing hormone (CRH) receptor antagonists, alpha-helical CRH [9-14], given i.c.v. did not alter the PGE(2)-evoked corticosterone response in either control or stressed rats, indicating that hypothalamic CRH is not involved in the PGE(2)-induced central stimulation of HPA axis. In control rats L-NAME considerably enhanced, while L-arginine, a physiological NOS substrate, abolished the PGE(2)-induced ACTH and corticosterone response. In stressed rats this NOS blocker significantly increased and L-Arg reduced the stimulatory effect of PGE(2) on ACTH and corticosterone secretion. The carbachol-induced corticosterone response was significantly increased by pretreatment with nNOS inhibitor L-NNA and was considerably reduced by indomethacin, a general COX inhibitor. Pretreatment with both antagonists left the carbachol-induced corticosterone level unchanged, suggesting an independent and reciprocal effect of NO and PG in the cholinergic stimulation of pituitary-adrenocortical response. These results indicate that in the stimulatory action of muscarinic agonist, carbachol, NO is an inhibitory transmitter under basal and crowding stress conditions. This psychosocial stress does not functionally affect the NOS/NO systems. Prostaglandins are involved in the cholinergic muscarinic-induced stimulation of HPA response to a significant extent in non-stressed rats. PGE(2) may be involved in the carbachol-elicited HPA response under basal and stress conditions. Prostaglandins released in response to muscarinic stimulation did not evoke the hypothalamic CRH mediation. NO significantly impairs and PG stimulates the carbachol-induced HPA response in rats under basal and social stress conditions.     

Lesions of the anteroventral third ventricle region (AV3V) disrupt cardiovascular responses to an elevation in core temperature

Blood flow is redistributed from the viscera to the periphery during periods of heat stress to maximize heat loss. The heat-induced redistribution of blood flow is strongly influenced by nonthermal inputs such as hydration status. At present, little is known about where thermal and nonthermal information is integrated to generate an appropriate effector response. Recently, the periventricular tissue that surrounds the anteroventral third ventricle (AV3V) has been implicated in the integration of thermal and osmotic information. The purpose of the present study was to determine the effects of electrolytic lesions of the AV3V on the cardiovascular response to a passive heat stress in unanesthetized, free-moving male Sprague-Dawley rats. Core temperature was elevated at a constant rate of approximately 0.03 degrees C/min in sham- and AV3V-lesion rats using an infrared heat lamp. Changes in mesenteric and hindquarter vascular resistance were determined using Doppler flow probes, and heat-induced salivation was estimated using the spit-print technique. The rise in mean arterial pressure (MAP), heart rate (HR), and mesenteric resistance in response to elevations in core temperature were all attenuated in AV3V-lesion rats; however, hindquarter resistance was unaffected. Heat-induced salivation was also diminished. In addition, AV3V-lesion rats were more affected by the novelty of the experimental environment, resulting in a higher basal core temperature, HR, and MAP. These results indicate that AV3V lesions disrupt the cardiovascular and salivatory response to a passive heat stress in rats and produce an exaggerated stress-induced fever triggered by a novel environment.     

Repeated handling, restraint, or chronic crowding impair the hypothalamic-pituitary-adrenocortical response to acute restraint stress.

The purpose of the present study was to assess whether, and to what extent prior handling, restraint or social crowding stress during 3-10 days affects the hypothalamic-pituitary-adrenocortical (HPA) response to an acute short-lasting restraint stress. Also the effect of a feedback inhibitory mechanism of corticosterone in the impairment of HPA axis by these stressors was investigated. Male Wistar rats were pretreated with handling 1 min/day for 3-10 days, restraint 2 times daily for 3-7 days and crowding stress for 7 days before exposure to acute restraint stress in metal tubes for 10 min. Some group of rats received exogenous s.c. corticosterone either once 25 mg/kg or 2 times daily 10 mg/kg for 3-10 days before restraint stress. After the last restraint the rats were decapitated and their trunk blood was collected for the measurement of plasma ACTH and serum corticosterone levels. Handling for 3-7 days, restraint for 3-7 days, and crowding for 7 days and a single pretreatment with corticosterone--all significantly and to a similar extent inhibited the restraint stress-induced increase in ACTH and corticosterone secretion. Chronic pretreatment with corticosterone blunted the restraint stress-induced increase in HPA axis activity. These results indicate that repeated short-lasting stress induced by handling, restraint, or crowding potently attenuates the acute restraint stress-induced stimulatory action of the HPA axis. They also indicate adaptive action of moderate stress on the HPA axis response to acute stress. The results also suggest that a short-lasting hypersecretion of corticosterone during psychological stress may induce a prolonged feedback inhibition of the HPA axis activity. The attenuation of HPA axis response by prior handling has also obvious methodological implications.     

Maternal glucocorticoid deficit affects hypothalamic-pituitary-adrenal function and behavior of rat offspring

Detrimental consequences of prenatal stress include increased hypothalamic-pituitary-adrenal (HPA) function, anxiety and depression-like behavior in adult offspring. To identify the role of maternal corticosterone milieu in the fetal programming of adult function, we measured these same behavioral and hormonal endpoints after maternal adrenalectomy (ADX) and replacement with normal or moderately high levels of corticosterone (CORT). Adult male and female offspring exhibited differing HPA responses to maternal ADX. In female offspring of ADX mothers, exaggerated plasma ACTH stress responses were reversed by the higher, but not the lower, dose of maternal CORT. In contrast, male offspring of both ADX and ADX dams with higher CORT replacement showed exaggerated ACTH stress responses. Hypothalamic glucocorticoid receptor (GR) expression was decreased in these latter groups, while hippocampal GR increased only in the ADX offspring. Activity of young offspring of ADX dams replaced with the higher dose of CORT decreased in the open field test of exploration/anxiety, while immobility behavior of adult offspring in the forced swim test of depression increased following maternal ADX or higher levels of CORT replacement. Interestingly, for some measures, none or moderately high CORT replacement resulted in similar deficits in this study. These findings are in accord with consequences of prenatal stress or prenatal dexamethasone exposure, suggesting that a common mechanism may underlie the effects of too low or too high maternal glucocorticoids on adult HPA function and behavior.     

Effect of aging on 24-hour pattern of stress hormones and leptin in rats

This work analyzes the 24-hour changes of hypothalamic-pituitary-adrenal (HPA) axis activity and leptin release in aged rats. Three- and 22-month-old male Wistar rats were killed at 6 time intervals during a 24-hour cycle (n=8-10 rats/group). Aging augmented plasma ACTH while it decreased plasma and adrenal gland corticosterone levels. Plasma and adrenal corticosterone levels attained high levels during all the scotophase, concomitantly with the maxima in ACTH levels, whereas in aged rats only a brief plasma corticosterone peak at the early scotophase and no time of day variations of adrenal corticosterone were observed. Aging augmented circulating leptin, with a significant interaction "agextime" in the factorial ANOVA, i.e. only in young rats time of day changes were significant, with the lowest values of leptin at the middle of the light period and higher values at night. When plasma leptin was expressed on body weight basis, the age-related differences became not significant but the daily pattern of plasma leptin found in young rats persisted. Plasma and adrenal corticosterone levels correlated significantly with plasma ACTH only in young rats. Likewise, plasma leptin correlated with plasma corticosterone only in young rats. These changes can be attributed to a disrupting effect of aging on the homeostatic mechanisms modulating HPA activity and leptin release.     

Adrenalectomy reduces exploratory activity in the rat: a specific role of corticosterone

The effect of chronic adrenalectomy (10 days) and subsequent steroid hormone administration on exploratory activity in male rats was studied. Chronic adrenalectomy significantly decreased ambulatory and rearing activities, while grooming and defecation scores were not affected. Subcutaneous administration of corticosterone (30 μg/100 g body wt) 1 hr before the open-field test restored the decreased exploratory behavior of adrenalectomized rats toward the activity observed in sham-operated control animals. Neither dexamethasone or progesterone were effective. Administration of the synthetic glucocorticoid 1 hr prior to corticosterone substitution of the adrenalectomized rats even resulted in a complete prevention of the normalization of the behavioral response. The observed specific action of corticosterone on exploratory behavior corresponds to the stringent specificity of the neuronal hippocampal corticosterone receptor system.     

Nitric oxide mediates the interleukin-1beta- and nicotine-induced hypothalamic-pituitary-adrenocortical response during social stress.

We investigated the role of nitric oxide (NO) in the interleukin 1beta (IL-1beta) and nicotine induced hypothalamic-pituitary-adrenal axis (HPA) responses, and a possible significance of CRH and vasopressin in these responses under basal and social stress conditions. Male Wistar rats were crowded in cages for 7 days prior to treatment. All compounds were injected i.p., nitric oxide synthase (NOS) inhibitors, alpha-helical CRH antagonist and vasopressin receptor antagonist 15 min before IL-1beta or nicotine. Identical treatment received control non-stressed rats. Plasma ACTH and serum corticosterone levels were measured 1 h after IL-1beta or nicotine injection. L-NAME (2 mg/kg), a general nitric oxide synthase (NOS) inhibitor, considerably reduced the ACTH and corticosterone response to IL-1beta (0.5 microg/rat) the same extent in control and crowded rats. CRH antagonist almost abolished the nicotine-induced hormone responses and vasopressin antagonist reduced ACTH secretion. Constitutive endothelial eNOS and neuronal nNOS inhibitors substantially enhanced the nicotine-elicited ACTH and corticosterone response and inducible iNOS inhibitor, aminoguanidine, did not affect these responses in non-stressed rats. Social stress significantly attenuated the nicotine-induced ACTH and corticosterone response. In crowded rats L-NAME significantly deepened the stress-induced decrease in the nicotine-evoked ACTH and corticosterone response. In stressed rats neuronal NOS antagonist did not alter the nicotine-evoked hormone responses and inducible NOS inhibitor partly reversed the stress-induced decrease in ACTH response to nicotine. These results indicate that NO plays crucial role in the IL-1beta-induced HPA axis stimulation under basal and social stress conditions. CRH and vasopressin of the hypothalamic paraventricular nucleus may be involved in the nicotine induced alterations of HPA axis activity. NO generated by eNOS, but not nNOS, is involved in the stress-induced alterations of HPA axis activity by nicotine.     

大鼠慢性多重应激模型的建立

目的:建立大鼠慢性多重应激模型,为研究应激性疾病提供实验模型.方法:健康雄性SD大鼠随机分为模型组(n=10)和对照组(n=10).模型组采用脉冲随机变动的噪声、夜间光照、足底电击以及强迫游泳和束缚的复合刺激为应激源,对大鼠实施刺激,观察行为变化,检测心率、血压、体重增长速率、食物利用率,测定血清ACTH和皮质酮并进行分析.结果:慢性多重应激大鼠由实验之初的兴奋状态逐渐进入抑制状态,血压心率上升,体重增长缓慢,食物利用率降低,血清ACTH和皮质酮增高.结论:慢性多重应激大鼠一般行为、基本生理体征和下丘脑-垂体-肾上腺轴(HPA)功能发生改变,应激反应处于持续亢奋状态,该模型是较稳定较理想的应激模型.     

CRF-dependent and CRF-independent mechanisms involved in hypophysial-adrenal system activation by bacterial endotoxin.

The immune system and the hypothalamic-pituitary-adrenal (HPA) axis play important role in the overall inflammatory response. The mechanism through which lipopolysaccharide (LPS, endotoxin) stimulates the HPA axis is not well understood. In order to clarify the role of hypophysiotropic peptides of paraventricular origin in the effect of LPS on ACTH and corticosterone secretion, the effect of LPS was studied on rats with lesions of hypothalamic paraventricular nucleus (PVN). It was shown that 90 min after 2 mg/kg LPS i.p. the ACTH, but not the corticosterone response was effectively blunted in PVN-lesioned rats, as compared to sham operated animals. However, in PVN-lesioned rats 240 min after treatment with LPS a significantly higher plasma ACTH and corticosterone level was monitored. It is, therefore, suggested that in response to LPS activation of HPA both CRF(s)-dependent and CRF(s)-independent mechanisms are involved, even a direct effect of the adrenal cortex should be taken into account.     

Periodic maternal deprivation and lesion of anterodorsal thalami nuclei induce alteration on hypophyso adrenal system activity in adult rats

The hypothalamic-pituitary-adrenal (HPA) axis is normally regulated by extrahypothalamic limbic structures, among these, the anterodorsal thalami nuclei (ADTN), which exert an inhibitory influence on HPA, in basal and acute stress conditions in rats. In the present work we have investigated whether neonatal maternal deprivation (MD) produces long-term changes in the ADTN regulation of HPA activity. Maternal deprivation, in female rats, for 4.5 hs daily, during the first 3 weeks of life, produced at 3 months old, a significant decrease in plasma ACTH concentration (p<0.001) and an increase in plasma corticosterone (C) (p<0.001), compared to control non-deprived rats (NMD). Also MD showed higher plasma epinephrine (E) and norepinephrine (NE) levels than NMD rats. The increase of NE (66.6% p<0.001) was higher than that observed in E (19%). After 30 days of ADTN lesion, plasma ACTH values were higher than in sham lesioned rats, in both NMD and MD animals. ACTH response was greater in MD rats. Plasma C, in NMD, was higher, whereas in MD lesioned animals, it was significantly lower than in sham lesioned. In MD rats, lesion produced a significant increase in plasma E and NE (p<0.001), and again, NE increase was higher than E increase. The more accentuated increase of NE than E, suggests sympathetic nervous system hyperactivity. In summary, neonatal maternal deprivation induces long-term alterations on HPA axis sensitivity and medullo adrenal secretion; enhanced sympathetic nervous system activity and, therefore affected the ADTN inhibitory influence on ACTH and adrenal glands secretion.     

What can we know from pituitary-adrenal hormones about the nature and consequences of exposure to emotional stressors?

Exposure to stress induces profound physiological and behavioral changes in the organisms and some of these changes may be important regarding stress-induced pathologies and animal models of psychiatric diseases. Consequences of stress are dependent on the duration of exposure to stressors (acute, chronic), but also of certain characteristics such as intensity, controllability, and predictability. If some biological variables were able to reflect these characteristics, they could be used to predict negative consequences of stress. Among the myriad of physiological changes caused by stress, only a restricted number of variables appears to reflect the intensity of the situation, mainly plasma levels of ACTH and adrenaline. Peripheral hypothalamic-pituitary-adrenal (HPA) hormones (ACTH and corticosterone) are also able to reflect fear conditioning. In contrast, the activation of the HPA axis is not consistently related to anxiety as evaluated by classical tests such as the elevated plus-maze. Similarly, there is no consistent evidence about the sensitivity of the HPA axis to psychological variables such as controllability and predictability, despite the fact that: (a) lack of control over aversive stimuli can induce behavioral alterations not seen in animals which exert control, and (b) animals showed clear preference for predictable versus unpredictable stressful situations. New studies are needed to re-evaluate the relationship between the HPA axis and psychological stress characteristics using ACTH instead of corticosterone and taking advantages of our current knowledge about the regulation of this important stress system.     

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.     

Effect of constitutive- and inducible-cyclooxygenase in the carbachol-induced pituitary-adrenocortical response during social stress.

Acetylcholine potently stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Cholinergic receptor agonist carbachol, given intraperitoneally (i.p.) or into the lateral cerebral ventricle (i.c.v.) to non-anesthetized rats acts via multiple pathways to stimulate the HPA axis. The present study sought to determine 1) the functional selectivity of carbachol for cholinergic muscarinic and/or nicotinic receptors involved in the stimulation of HPA axis; 2) the involvement of prostaglandins (PGs) generated by constitutive and inducible cyclooxygenase (COX-1 and COX-2) in the carbachol-induced ACTH and corticosterone secretion in non-stressed rats and animals exposed to social crowding stress for 7 days (24 per a cage for 6). Carbachol was given i.c.v. or i.p. and cholinergic receptor antagonists or cyclooxygenase isoenzyme antagonists were given by the same routes 15 min earlier. One hour after the last injection trunk blood was taken for ACTH and corticosterone determinations. Atropine (0.1 microg i.c.v.), a cholinergic receptor antagonist, totally abolished the carbachol (2 microg i.c.v.)-induced ACTH and corticosterone secretion and mecamylamine (20 microg i.c.v.), a selective nicotinic receptor antagonist, did not affect this secretion. This finding indicates that carbachol functions as a selective central cholinergic muscarinic receptor agonist for the HPA axis stimulation. Crowding stress significantly diminished the carbachol (0.2 mg/kg i.p.)-induced plasma ACTH and corticosterone levels measured 1 hr after administration. Pretreatment with indomethacin (2 mg/kg i.p.), a non-selective cyclooxygenase inhibitor, significantly diminished the ACTH and corticosterone responses to carbachol (0.2 mg/kg i.p.) in control rats and moderately decreased these responses in stressed rats. Piroxicam (0.2 and 2.0 mg/kg i.p.), a COX-1 inhibitor, considerably impaired the carbachol-induced ACTH and corticosterone responses in control rats and markedly diminished these responses in stressed rats. A selective COX-2 blocker, compound NS-398 (0.2 and 2.0 mg/kg i.p.), substantially decreased the carbachol-induced hormones secretion in control rats but did not markedly alter this secretion in stressed rats. These results indicate that in the carbachol-induced HPA axis activation PGs generated by COX-1 are considerably and to a much greater extent involved than PGs generated by COX-2. Social stress markedly diminishes the mediation of PGs generated by COX-1 but PGs synthesized by COX-2 do not substantially participate in the carbachol-induced HPA response.     

A single corticosterone pretreatment inhibits the hypothalamic-pituitary-adrenal responses to adrenergic and cholinergic stimulation.

The purpose of the present study was to determine whether an increased plasma corticosterone or dexamethasone levels induced by a single corticosterone or dexamethasone injection to conscious rats affects the hypothalamic-pituitary-adrenocortical (HPA) activity induced by adrenergic and cholinergic agonists. Male Wistar rats were pretreated subcutaneously (s.c.) with a single dose of dexamethasone (5 mg/kg) or corticosterone (25 mg/kg) 24 or 48 h before intraperitoneal (i.p.) administration of adrenergic agonists: phenylephrine, an alpha1-adrenergic receptor agonist, clenbuterol, a beta2-adrenergic agonist and noradrenaline acting predominantly on alpha1-adrenoreceptors, and cholinergic agonists: carbachol, a predominant muscarinic receptor agonist and nicotine, a nicotinic receptor agonist. Dexamethasone profoundly decreased the resting ACTH levels in control rats and given 24 h before each of the stimulatory agonist abolished the adrenergic- and cholinergic agonists-induced ACTH and corticosterone responses. Pretreatment with corticosterone of control rats did not substantially alter the resting plasma ACTH and serum corticosterone levels measured 24 and 48 h later. A single pretreatment with corticosterone abolished or powerfully inhibited, perhaps by a feedback mechanism, the ACTH and corticosterone responses induced 24 and 48 h later by all adrenergic and cholinergic agonists used in this study. These results indicate that prolonged administration of corticosterone is not necessary to induce almost complete suppression of the HPA responsiveness to adrenergic or cholinergic stimulation. Chronic treatment with corticosteroids to achieve glucocorticoid receptors desensitization does not seem to be required.     

Role of nitric oxide in the nicotine-induced pituitary-adrenocortical response.

Nitric oxide (NO) is a major signaling molecule and biological mediator of the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the role of NO formed by endothelial (e), neuronal (n) and inducible (i) nitric oxide synthase (NOS) in the stimulatory effect of nicotine on the HPA axis in rats under basal conditions. Also possible interaction of NOS systems with endogenous prostaglandins (PG) in that stimulation was assessed. NOS and cyclooxygenase inhibitors were administered i.p. 15 min prior to nicotine (2, 5 mg/kg i.p.). Plasma ACTH and serum corticosterone levels were measured 1 h after nicotine injection. NOS blockers given alone did not markedly affect the resting ACTH and corticosterone levels. L-NAME (2-10 mg/kg), a broad spectrum NOS inhibitor considerably and dose dependently enhanced the nicotine-induced ACTH and corticosterone secretion. L-NNA (2 mg/kg) and 7-nitroindazole (7-NI 20 mg/kg), neuronal NOS inhibitors in vivo also significantly augmented the nicotine-induced ACTH and corticosterone levels. L-arginine greatly impaired the nicotine-induced hormone responses and reversed the L-NNA elicited enhancement of the nicotine-evoked ACTH and corticosterone response. In contrast to the constitutive eNOS and nNOS antagonists, an inducible NOS antagonist guanethidine (50-100 mg/kg i.p.) did not substantially affect the nicotine-elicited pituitary-adrenocortical responses. Indomethacin (2 mg/kg i.p.), a non-selective cyclooxygenase blocker abolished the L-NAME and L-NNA-induced enhancement of the nicotine-evoked ACTH and corticosterone response. These results indicate that NO is an inhibitory mediator in the HPA axis activity. Inhibition of its generation by eNOS and nNOS significantly enhances the nicotine-induced HPA response. Under basal conditions iNOS is not involved in the nicotine-induced ACTH and corticosterone secretion. Prostaglandins play an obligatory role in the response of HPA axis to systemic nicotine administration.     

Paternal behavior influences development of aggression and vasopressin expression in male California mouse offspring

Parental care has been demonstrated to have important effects on offspring behavioral development. California mice (Peromyscus californicus) are biparental, and correlational evidence suggests that pup retrieving by fathers has important effects on the development of aggressive behavior and extra-hypothalamic vasopressin systems. We tested whether retrievals affected these systems by manipulating paternal retrieval behavior between day 15 and 21 postpartum. Licking and grooming behavior affect behavioral development in rats, so we also experimentally reduced huddling and grooming behavior by castrating a subset of fathers. Experimentally increasing the frequency of paternal pup retrieving behavior decreased attack latency in resident-intruder in both male and female adult offspring, whereas experimental reduction of huddling and grooming had no effect. In a separate group of male offspring, we examined vasopressin immunoreactivity (AVP-ir) in two regions of the posterior bed nucleus of the stria terminalis (BNST): the dorsal fiber tracts (dBNST) and the ventral cell body-containing region (vBNST). Experimentally increasing retrievals led to an apparent shift in AVP-ir distribution. Specifically, offspring from the high retrieval group had more AVP-ir than offspring from the sham retrieval group in the dBNST, whereas the opposite was observed in the vBNST. Experimental reduction of paternal grooming was associated with increased AVP-ir in the paraventricular nucleus and also increased corticosterone and progesterone, similar to observed effects of maternal grooming on HPA function. This study provides further evidence that paternal behavior influences the development of aggression and associated neural substrates.