Effect of pentylenetetrazol on the carbaryl-induced changes of serotonin metabolism in rat-brain hypothalamus

Carbaryl (200 mg/kg or 400 mg/kg, p.o.) significantly elevated serotonin (5-HT) (57–109%) and 5-hydroxy-indoleacetic acid (5-HIAA) (60–78%) levels at 1.0 h in the hypothalamic region of adult male rat brain. Further, administration of carbaryl (200 mg/kg, p.o.) for different time intervals (0.5 h, 1.0 h, and 2.0 h) revealed that both 5-HT and 5-HIAA levels elevated maximally at 0.5 h in hypothalamus. These regional 5-HT and 5-HIAA levels were not significantly affected with pentylenetetrazol (PTZ) at any time after its treatment. But simultaneous administration of carbaryl (200 mg/kg, p.o.) and PTZ (60 mg/kg, s.c.) reduced the carbaryl-induced elevation of both 5-HT and 5-HIAA leveis. Measurement of (i) probenecid-induced (200 mg/kg, i.p.) accumulation and (ii) pargyline-induced (75 mg/kg, i.p.) depletion of hypothalamic 5-HIAA level in the absence or presence of carbaryl (200 mg/kg, p.o.) and/or PTZ (60 mg/kg, s.c.) revealed that (a) carbaryl enhanced the synthesis as well as the breakdown of 5-HT, (b) PTZ had no effect on either of these processes of 5-HT, and (c) carbaryl-induced increased catabolism of 5-HT became normal in the presence of PTZ.     

24-hour rhythms in oxidative stress during hepatocarcinogenesis in rats: effect of melatonin or alpha-ketoglutarate

To compare the effects of alpha-ketoglutarate (alpha-KG) and melatonin on 24-h rhythmicity of oxidative stress in N-nitrosodiethylamine (NDEA)-injected Wistar male rats, melatonin (5 mg/kg i.p.) or alpha-KG (2 g/kg through an intragastric tube) was given daily for 20 weeks. In blood collected at 6 time points during a 24-h period, serum activity of aspartate transaminase (AST) and alanine transaminase (ALT) and the levels of alpha-fetoprotein (alpha-FP) were measured as markers of liver function. To assess lipid peroxidation and the antioxidant status, plasma levels of thiobarbituric acid reactive substances (TBARS) and of reduced glutathione (GSH) were measured, together with the activity of erythrocyte superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST). NDEA augmented mesor and amplitude of rhythms in AST and ALT activity and plasma alpha-FP levels and mesor values of plasma TBARS, while decreasing mesor values of plasma GSH and erythrocyte SOD, CAT, GPx and GST. Acrophases were delayed by NDEA in all cases except for alpha-FP rhythm, which became phase-advanced. Co-administration of melatonin or alpha-KG partially counteracted the effects of NDEA. Melatonin decreased mesor of plasma TBARS and augmented mesor of SOD activity. The results indicate that melatonin and alpha-KG are effective in protecting from NDEA-induced perturbation of 24-h rhythms in oxidative stress. Melatonin augmented antioxidant defense in rats.     

Abnormal regulation of adrenal function in rats with streptozotocin diabetes.

The factors that control adrenal steroid secretion and metabolism were investigated in rats made diabetic with Streptozotocin (65 mg/kg) and used one month after treatment. Diabetic animals possessed high resting levels of plasma corticosterone accompanied by adrenal hypertrophy; the showed an increased response to the stress of i.p. cold water injection. Moreover, the pituitaries of diabetic rats seemed to be releasing ACTH continuously and not storing it. Upon adrenal inhibition with Aminoglutethimide the expected increase in adrenal cholesterol and weight was of a smaller magnitude than in controls. The activity of liver enzymes that reduce ring A of corticosterone showed decreased activity in diabetics, which suggests that more corticosterone rather than its inactive metabolites were available to--but not able to suppress--the steroid feedback sites. The half-life of corticosterone in blood was similar in diabetes and controls. These results suggest that (a) diabetic animals were in a chronic stress condition; (b) the threshold for steroid feedback was less sensitive to variations in plasma corticosterone; (c) there is an abnormal peripheral disposal of corticosterone, but that other factors, besides the liver, regulate the clearance of the hormone from the circulation in the diabetic animals.     

Stress-induced changes of glucocorticoid receptor in rat liver.

The effect of corticosterone injection and of acute and repeated stress on rat liver cytosol glucocorticoid receptor was studied to ascertain whether corticosterone-induced glucocorticoid receptor (GR) regulation also takes place in intact animals as it does in adrenalectomized ones. Adult male rats were exposed to six different stressors (swimming, 10 mg/kg histamine i.p., 500 mU/kg vasopressin s.c., heat, immobilization and cold) acutely or three times daily for 18 days (repeated stress). Each of the stressors applied acutely provoked a pronounced increase of plasma corticosterone with subsequent induction of hepatic tyrosine aminotransferase activity. Depletion of cytosol receptor was however only noticed after swimming and histamine injection. On the other hand, sustained hypersecretion of corticosterone evoked by repeated stress significantly reduced the number of GR in rat liver cytosol without any change in Kd. It is concluded that in the presence of intact adrenal glands cytosol receptors are more resistant to corticosterone-induced depletion than in their absence. Further, repeated stress causes down-regulation of GR in the liver, most probably by sustained corticosterone secretion, yet the effect of other stress factors cannot be excluded.     

Adaptogenic activity of Siotone, a polyherbal formulation of Ayurvedic rasayanas

Siotone (ST) is a herbal formulation comprising of Withania somnifera, Ocimum sanctum, Asparagus racemosus, Tribulus terristris and shilajit, all of which are classified in Ayurveda as rasayanas which are reputed to promote physical and mental health, improve defence mechanisms of the body and enhance longevity. These attributes are similar to the modern concept of adaptogenic agents, which are, known to afford protection of the human physiological system against diverse stressors. The present study was undertaken to investigate the adaptogenic activity of ST against chronic unpredictable, but mild, footshock stress induced perturbations in behaviour (depression), glucose metabolism, suppressed male sexual behaviour, immunosuppression and cognitive dysfunction in CF strain albino rats. Gastric ulceration, adrenal gland and spleen weights, ascorbic acid and corticosterone concentrations of adrenal cortex, and plasma corticosterone levels, were used as the stress indices. Panax ginseng (PG) was used as the standard adaptogenic agent for comparison. Additionally, rat brain levels of tribulin, an endogenous endocoid postulated to be involved in stress, were also assessed in terms of endogenous monoamine oxidase (MAO) A and MAOB inhibitory activity. Chronic unpredictable footshock induced marked gastric ulceration, significant increase in adrenal gland weight and plasma corticosterone levels, with concomitant decreases in spleen weight, and concentrations of adrenal gland ascorbic acid and corticosterone. These effects were attenuated by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.), administered once daily over a period of 14 days, the period of stress induction. Chronic stress also induced glucose intolerance, suppressed male sexual behaviour, induced behavioural depression (Porsolt's swim despair test and learned helplessness test) and cognitive dysfunction (attenuated retention of learning in active and passive avoidance tests), and immunosuppression (leucocyte migration inhibition and sheep RBC challenged increase in paw oedema in sensitized rats). All these chronic stress-induced perturbations were attenuated, dose-dependently by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.). Chronic stress-induced increase in rat brain tribulin activity was also reversed by these doses of ST and by PG. The results indicate that ST has significant adaptogenic activity, qualitatively comparable to PG, against a variety of behavioural, biochemical and physiological perturbations induced by unpredictable stress, which has been proposed to be a better indicator of clinical stress than acute stress parameters. The likely contribution of the individual constituents of ST in the observed adaptogenic action of the polyherbal formulation, have been discussed.     

Effect of L-NAME, a specific nitric oxide synthase inhibitor, on corticotropin-releasing hormone-elicited ACTH and corticosterone secretion.

This study was designed to determine the role of endogenous nitric oxide (NO) in the corticotropin-releasing hormone (CRH)-induced ACTH and corticosterone secretion, as well as possible involvement of hypothalamic dopamine and noradrenaline in that secretion in conscious rats. CRH given i.p. stimulated dose-dependently the pituitary-adrenocortical activity measured 1 h later. Dexamethasone (0.2 mg/kg i.p.) injected 1 h before CRH (1 microg/kg i.p.) totally abolished the CRH-elicited ACTH and corticosterone secretion, indicating a predominantly pituitary site of CRH-evoked stimulation. L-arginine (120 mg/kg i.p.) and N(omega)-nitro-L-arginine methyl ester (L-NAME 5-10 mg/kg i.p.) did not markedly affect the basal plasma ACTH and corticosterone levels. L-NAME given 15 min before CRH markedly, but not significantly, augmented the CRH-induced ACTH response, and enhanced more potently and significantly the corticosterone response. Pretreatment with L-arginine, a substrate for NOS, slightly diminished the CRH-induced ACTH response and considerably reduced the corticosterone response. L-arginine also significantly reversed the L-NAME-evoked increase in the CRH-induced ACTH and corticosterone secretion. L-NAME did not markedly alter the CRH-induced hypothalamic dopamine and noradrenaline levels, while L-arginine significantly increased noradrenaline level. However, those alterations were not directly correlated with the observed changes in ACTH and corticosterone secretion. These results indicate that in conscious rats NO plays a marked inhibitory role in the CRH-induced ACTH secretion and inhibits more potently corticosterone secretion. Hypothalamic dopamine and noradrenaline do not seem to be directly involved in the observed alterations in ACTH and corticosterone secretion.     

Synthesis of rat hepatic zinc thionein in response to the stress of sham operation

Following sham operation for adrenalectomy, a dramatic 30-fold increase in rat hepatic zinc thionein occurs, peaking at 18 hours after surgery. Hepatic cytosolic and serum zinc levels rise concomitantly with zinc thionein. Copper in hepatic thionein and cytosol rises only slightly and serum copper not at all during the period of observation. In the period 18 to 48 hours after surgery the content of hepatic zinc thionein decreases with a $\text{t}\text{1}\text{2}$ of 16.4 hours.Pretreatment with cycloheximide (1 mg/kg b.w.) two hours before surgery inhibits the rise in zinc thionein by 52%, the rise in cytosolic zinc by 56%, and actually causes a decrease in serum zinc by 33%. Pretreatment with the α-adrenergic receptor blocker, phetolamine (10 mg/kg b.w.), or the β-adrenergic receptor blocker, propranolol (10 mg/kg b.w.), 30 minutes before surgery also inhibited the rise in zinc thionein (82% and 60%, respectively) and cytosolic zinc (75% and 47%, respectively), and decreased serum zinc (38% and 44%, respectively) 19 hours after surgery.Treatment with corticosterone (40 mg/kg b.w.) alone or epinephrine (1–20 μg/kg b.w.) alone did not alter hepatic zinc thionein levels 18 hours late, although they each caused hypozincemia and epinephrine raised cytosolic zinc levels. Treatment with corticosterone and epinephrine together did, however, raise zinc thionein levels 3.2-fold (P<0.02).These experiments are consistent with the hypothesis that adrenal hormones are involved in the regulation of zinc metabolism, and, hence, zinc thionein in levels in rat liver following the stress of sham operation.     

ACTH and corticosterone response to naloxone and morphine in normal, hypophysectomized and dexamethasone-treated rats

The effect of opiate receptors blocker naloxone on ACTH and corticosterone secretion in normal, dexamethasone-treated and hypophysectomized rats was studied. A dose-related increase in plasma corticosterone level was found at 45 min after s.c. injection of naloxone in a dose range of 0.25-2.0 mg kg-1. The rise in plasma corticosterone was preceded by a slight increase in plasma ACTH. Acute morphine administration in a relatively low dose (6 mg kg-1 s.c.) induced a significant rise in both plasma ACTH and corticosterone levels. Dexamethasone treatment was followed by low basal corticosterone level, by total inhibition of the stress response and response to morphine injection, while the response to ACTH administration was normal. Under these circumstances as well as in rats 6 days after hypophysectomy, naloxone failed to increase plasma corticosterone levels. It is concluded that a direct stimulation of corticosteroid biosynthesis in adrenal cortex is not involved in the mechanism of naloxone-induced activation of pituitary-adrenocortical function.     

Mechanism of bromocriptine-induced hyperglycaemia

Results reveal that bromocriptine at a dose of 6 mg/kg. I.P. in mice caused a significant hyperglycaemic effect which was accompanied by a marked increase in liver glycogen. After adrenalectomy, the effect of bromocriptine on serum glucose level was reduced whereas its effect on liver glycogen content was abolished. In rats, administration of bromocriptine (17.5 mg/kg I.P.) induced a significant rise in serum glucose level which was associated with marked reduction in serum insulin activity and increase in serum corticosterone level with no effect on serum triiodothyronine (T3) or thyroxine (T4) levels. It could be concluded that bromocriptine-induced hyperglycaemia might be attributed at least partially to inhibition of insulin release and stimulation of corticosterone secretion.     

Paracetamol and conventional antimalarial drugs induced hepatotoxicity and its protection by methionine in rats

Hepatotoxicity, induced in rats, by treatment with high doses of paracetamol and chloroquine was confirmed by estimating blood transaminase levels. Hepatoprotective effect was determined by administering combination of methionine (10% of paracetamol/chloroquine, p.o.) and hepatotoxic drugs quinine. The results were confirmed by histopathological examination of liver. Paracetamol (7 g/kg) and chloroquine (970 mg/kg) administration increased significantly the transaminase levels. Methionine alone did not produced any change. Hepatonecrosis induced by paracetamol, chloroquine alone and their combinations and its protection with methionine was revealed by histopathological study whereas the combination of paracetamol and methionine showed no significant histopathological difference when compared to the normal liver section. The results reveal that, methionine significantly prevented the rise in transaminases levels produced by hepatotoxic doses of paracetamol and chloroquine. But, to prevent occasional cases of paracetamol overdosage, it is not advisable to give methionine concurrently with paracetamol to patients who are taking paracetamol therapeutically.     

Memory Enhancing Activity of Naringin in Unstressed and Stressed Mice: Possible Cholinergic and Nitriergic Modulation

The present study was designed to evaluate the effect of Naringin on memory of unstressed and stressed Swiss young albino mice. Naringin (80?mg/kg, i.p.) and donepezil (10?mg/kg) were administered for 21 successive days to separate groups of unstressed and stressed mice. The nootropic activity was evaluated using elevated plus maze and Hebbs Williams Maze. Brain acetylcholinesterase (AChE), brain nitrite and plasma corticosterone levels were also estimated. unpredictable chronic mild stress was produced by using different stressors. Naringin (80?mg/kg) and donepezil significantly showed memory enhancing activity in both unstressed and stressed mice. Naringin significantly reduced brain AChE activity and brain nitrite levels in both unstressed and stressed mice. Naringin (80?mg/kg) significantly reversed scopolamine-induced amnesia in unstressed and stressed mice. 7-Nitroindazole [a neuronal nitric oxide synthase (NOS) inhibitor] and aminoguanidine (an inducible NOS inhibitor) significantly enhanced memory improving activity and brain nitrite decreasing effect of naringin in unstressed and stressed mice respectively. Plasma corticosterone levels were significantly decreased by naringin (80?mg/kg) in stressed mice as compared to its control. Thus, naringin showed memory enhancing activity in unstressed mice probably by decreasing brain AChE activity and by inhibition of neuronal NOS. The memory enhancing activity of naringin in stressed mice might be due to decrease in brain AChE activity, inhibition of inducible NOS and also by decreasing the elevated plasma corticosterone levels.     

Brain histamine-plasma corticosterone interactions

Significant elevation in plasma corticosterone of rats achieved by intraperitoneal (i.p.) administration of corticosterone (2.4 mg/kg) was associated with a rapid (2.5 min) and significant increase in hypothalamic histamine (HA) levels which persisted for 60 min. Midbrain and cortical HA concentrations were not affected. Significant and prolonged elevation of hypothalamic, midbrain and cortical HA levels was achieved by L-histidine administration (500 mg/kg i.p.). The most significant increase was noted in the hypothalamus and persisted for 10 hours. The elevated brain HA levels were associated with significant increase in plasma corticosterone levels which lasted for 120 mins. Present data supports the involvement of central HA in endocrine function.     

Antianxiety-Like Activity of Gallic Acid in Unstressed and Stressed Mice: Possible Involvement of Nitriergic System

The aim of present study was to evaluate antianxiety-like activity of gallic acid in Swiss young male albino mice; and to explore the possible underlying mechanisms for this activity. Gallic acid (5, 10, 20 mg/kg, i.p.) and alprazolam (0.25 mg/kg, i.p.) were administered for 10 successive days to separate groups of mice. On 10th day, 45 min after the drug administration, stress was produced by immobilization of mice for 150 min and these mice were called as stressed mice. Anxiolytic activity was evaluated using elevated plus maze and light–dark test. The plasma nitrite and corticosterone levels were also estimated in unstressed and stressed mice. Effects of 7-nitroindazole (neuronal NOS inhibitor) and aminoguanidine (inducible NOS inhibitor) on antianxiety-like activity of gallic acid were also evaluated. Gallic acid (10 and 20 mg/kg) and alprazolam per se significantly showed antianxiety-like activity in both unstressed and stressed mice. The drugs did not show any significant effect on locomotor activity of the mice. Gallic acid significantly decreased the plasma nitrite levels in both unstressed and stressed mice. 7-nitroindazole and aminoguanidine significantly enhanced antianxiety-like activity and plasma nitrite decreasing effect of gallic acid in unstressed and stressed mice respectively. Plasma corticosterone levels were significantly decreased by gallic acid in stressed mice as compared to its control. Thus, gallic acid showed antianxiety-like activity in unstressed mice probably by inhibition of nNOS. On the other hand, antianxiety-like activity in stressed mice might be through inhibition of iNOS and reduction of plasma corticosterone levels.     

Caffeine inhibits the development of Ehrlich ascites carcinoma cells in female mice

Long-term administration of caffeine at a dose of 20 mg /kg/day p.o. suppressed the viability, oxygen consumption and [3H]-thymidine incorporation of Ehrlich ascites carcinoma (EAC) cells. Though no significant change in the levels of plasma and adrenal corticosterone as well as both total and reduced adrenal ascorbic acid were observed following long-term caffeine consumption, pretreatment of caffeine and continuation of its treatment in the course of development of EAC cells restored the EAC Cell-induced changes in both corticosterone and ascorbic acid levels to control values. These results, thus, suggest that caffeine may suppress the growth of EAC cells by modulating the adrenal ascorbate level as well as corticosterone status.     

Influence of nitric oxide synthase inhibitors on the vasopressin-induced pituitary-adrenocortical activity and hypothalamic catecholamine levels.

In the present study the role of endogenous nitric oxide (NO) in the vasopressin-induced ACTH and corticosterone secretion was investigated in conscious rats. Vasopressin (AVP 5 microg/kg i.p.) considerably augmented ACTH and corticosterone secretion. L-arginine (120 and 300 mg/kg i.p.) did not significantly alter the AVP-induced secretion of those hormones. Nitric oxide synthase (NOS) blockers N(omega)-nitro-L-arginine (L-NNA) and its methyl ester (L-NAME) given i.p. 15 min before AVP markedly increased the AVP-induced ACTH secretion. L-NNA (2 mg/kg) more potently and significantly increased the AVP-induced ACTH secretion, whereas L-NAME elicited a weaker and not significant effect. Both those NOS antagonists intensified significantly and to a similar extent the AVP-induced corticosterone secretion. L-arginine (120 mg/kg i.p.) reversed the L-NNA-induced rise in the AVP-stimulated ACTH secretion and substantially diminished the accompanying corticosterone secretion. Neither vasopressin alone nor in combination with L-arginine and L-NAME evoked any significant alterations in the hypothalamic noradrenaline and dopamine levels. L-NNA (2 and 10 mg/kg i.p.) elicited a dose dependent and significant decrease in the hypothalamic noradrenaline level. The hypothalamic dopamine level was not significantly altered by any treatment. These results indicate that in conscious rats endogenous NO has an inhibitory influence on the AVP-induced increase in ACTH and corticosterone secretion. L-NNA is significantly more potent than L-NAME in increasing the AVP-induced ACTH secretion. This may be connected with a considerable increase by L-NNA of hypothalamic noradrenergic system activation which stimulates the pituitary-adrenal axis in addition to specific inhibition of NOS.     

The non-benzodiazepine anxiolytic buspirone inhibits stress-induced renin secretion and lowers heart rate

The non benzodiazepine drug, buspirone, produces a dose-dependent biphasic effect on plasma renin activity in non-stressed rats. Low doses (0.1 - 2.0 mg/kg i.p.) decrease while high doses (10.0 - 50.0 mg/kg i.p.) increase plasma renin activity. The maximal decrease in plasma renin activity produced by buspirone (1.0 mg/kg i.p.) was observed 30 minutes post-injection. In addition, buspirone (0.5 and 2.0 mg/kg i.p.) blocked the stress-induced rise in plasma renin activity. This effect of buspirone is in contrast to the previously observed failure of the benzodiazepine anxiolytics to alter the effect of stress on plasma renin activity. Administration of buspirone (0.5 mg/kg i.p.) produced a sustained reduction (15%) in heart rate but did not affect mean arterial pressure. The present data support the view that the mechanism of the anxiolytic action of buspirone is different from that of the benzodiazepines.     

Role of prostaglandins and nitric oxide in the lipopolysaccharide-induced ACTH and corticosterone response.

This study was designed to determine the role of endogenous prostaglandins (PG) and nitric oxide (NO) in the lipopolysaccharide (LPS)-induced ACTH and corticosterone secretion in conscious rats. LPS (0.5 and 1 mg/kg) given i.p. stimulated the hypothalamic-pituitary-adrenocortical (HPA) activity measured 2 h later. A non-selective cyclooxygenase inhibitor indomethacin (10 mg/kg i.p.), piroxicam (2 mg/kg i.p.), a more potent antagonist of constitutive cyclooxygenase (COX-1) and compound NS-398 (2 mg/kg i.p.), a selective inhibitor of inducible cyclooxygenase (COX-2) given 30 min before LPS (1 mg/kg i.p.) significantly diminished both the LPS-induced ACTH and corticosterone secretion. COX-2 blocker was the most potent inhibitor of ACTH secretion (72.3%). Nomega-nitro-L-arginine methyl ester (L-NAME 2 and 10 mg/kg i.p.), a non-selective nitric oxide synthase (NOS) blocker given 15 min before LPS did not substantially alter plasma ACTH and corticosterone levels 2 h later. Aminoguanidine (AG 100 mg/kg i.p.), a selective inducible nitric oxide synthase (iNOS) inhibitor, considerably enhanced ACTH and corticosterone secretion induced by a lower dose (0.5 mg/kg) of LPS and did not significantly alter this secretion after a larger dose (1 mg/kg) of LPS. L-NAME did not markedly affect the indomethacin-induced inhibition of ACTH and corticosterone response. By contrast, aminoguanidine abolished the indomethacin-induced reduction of ACTH and corticosterone secretion after LPS. These results indicate an opposite action of PG generated by cyclooxygenase and NO synthesized by iNOS in the LPS-induced HPA-response.     

Analysis of the mechanism of the stress-protective action of delta sleep-inducing peptide

By RIA there were studied the contents of corticosterone, ACTH, beta-endorphin and insulin in the blood plasma, met- and leu-enkephalin in different regions of the rat brain and in the adrenal glands after a 6-hour immobilization. The stress increased the content of corticosterone, ACTH, beta-endorphin, but not insulin in the blood plasma, and the levels of met-enkephalin in the adrenal glands, but decreased the met-enkephalin contents in the striatum. The injection of DSIP (0.1 mg/kg, i/p) blocked partly the elevation of corticosterone only. The authors propose, that stress-protective action of DSIP is realized with the involvements of the hypothalamo-pituitary-adrenal gland system.     

Naloxone does not antagonize PCP-induced stimulation of the pituitary-adrenal axis in the rat

Phencyclidine (PCP) has been shown to stimulate the pituitary-adrenal axis in the rat. The purpose of the present study was to determine whether opiate receptors are involved in this effect by testing whether pretreatment with the opiate antagonist naloxone can antagonize PCP-induced ACTH and corticosterone release. PCP (10.0 mg/kg) produced increases in plasma ACTH and corticosterone 60 min after s.c. administration. Pretreatment with naloxone (2.0 mg/kg s.c.) did not reduce the rise in plasma levels of ACTH or corticosterone produced by PCP. These results indicate that naloxone-sensitive opiate receptors are not involved in the PCP-induced stimulation of the pituitary-adrenal axis in rats.     

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.