Effects of chlordiazepoxide, flumazenil and DMCM on plasma catecholamine and corticosterone concentrations in rats.

The effects of drugs representing three classes of benzodiazepine (BDZ) receptor-acting agents on circulating corticosterone (CS), noradrenaline (NA) and adrenaline (A) were examined in unstressed rats. Intragastric administration of a single-dose of the inverse agonist 3-carbomethoxy-4-ethyl-6,7-dimethoxy-beta-carboline (DMCM; 10 mg/kg) evoked 15-, 4- and 1.5-fold increases in plasma CS, A and NA, respectively, as compared to control values. The DMCM-induced CS, A and NA rises were completely blocked by combined treatment with the BDZ antagonist flumazenil (Ro 15-1788; 20 mg/kg). Flumazenil given alone did not affect plasma hormone levels. Administration (either intragastrically or intraperitoneally) of a single-dose of the BDZ agonist chlordiazepoxide (CDP; 20 mg/kg) produced a 10- to 15-fold increase in plasma CS but caused no change in plasma NA and A contents. Pretreatment with flumazenil blocked the CDP-elicited release of CS. The findings indicate that the CNS mechanisms controlling pituitary-adrenocortical and sympatho-adrenal outflow under basal conditions are functionally linked to central-type BDZ receptor system(s). Drugs with agonist or inverse-agonist actions at these receptor sites can be differentiated from each other by their distinct effects on plasma NA and A, but not CS, release.     

Effects of chlorfenvinphos on plasma corticosterone and aldosterone levels in rats

Plasma corticosteroids concentrations, in rats intoxicated with chlorfenvinphos (p.o. single dose 6.15 mg/kg), were investigated. A significant increase of corticosterone was observed at 1 and 3 h and aldosterone from 1 to 6 h after treatment. Brain and blood AChE activity was diminished to about 10–30% for up to 24 h, with maximal inhibition in brain at 2 h after treatment. Maximal increase in plasma corticosteroids levels occured within 1 h, while the brain AChE was only slightly inhibited at that time. Results suggest that changes in plasma corticosteroids are not related to the decrease of AChE activity in brain.     

Effect of the anxiolytic drug buspirone on prolactin and corticosterone secretion in stressed and unstressed rats

Buspirone is an atypical anxiolytic drug that exerts its action at a receptor site other than the GABA-benzodiazepine-chloride ionophore complex. The present study examined the effect of buspirone on plasma prolactin and corticosterone levels in both control and stressed rats. In unstressed rats, buspirone produced dose-dependent increases in plasma prolactin and corticosterone levels. The minimal doses of buspirone which led to significant elevations in plasma prolactin and corticosterone levels were 1.0 and 2.0 mg/kg (IP), respectively. The effect of buspirone on both hormones was maximal 30 minutes after injection. The plasma levels of prolactin and corticosterone were significantly elevated in rats that were stressed using a conditioned fear paradigm. Buspirone produced a dose-dependent attenuation of the stress-induced increase in prolactin secretion. The stress-induced increase in corticosterone secretion was inhibited by the 0.5 mg/kg (IP) dose but not by the 2.0 mg/kg (IP) dose of buspirone, which increased corticosterone secretion both in stressed and unstressed rats. These data suggest that the effect of buspirone on plasma prolactin and corticosterone levels may be mediated by two different mechanisms of action.     

Effects of nicotine on plasma corticosterone and brain amines in stressed and unstressed rats.

The administration of nicotine (0.4 mg/kh) to unstressed rats caused a rise in plasma corticosterone which persisted for 60 minutes and a fall in hippocampal 5-hydroxytryptamine (5-HT) at 45 minutes followed by a rise at 60 minutes. In rats which were stressed by being placed on an elevated platform, nicotine caused a reduction in hippocampal 5-HT at 45 and 75 minutes but did notaffect the plasma corticosterone concentration. Rats studied 16 hours after the last injection of a course of treatment with metypone had much reduced levels of plasma corticosterone and hippocampal 5-HT. Under the present conditions metyrapone also much diminished the effects of nicotine on plasma corticosterone levels in unstressed rats but had little effect on the response to stress.     

A comparison of the effects of buspirone and diazepam on plasma corticosterone levels in rat

The effect of the anxiolytic agents, buspirone and diazepam, on the hypothalamic-pituitary-adrenal axis (HPAA), indicated by changes in the concentration of corticosterone (CS) in plasma, were studied 1/2, 1, 2, 4, 6, 8 and 24 hr after administration of the drug (i.p.). Samples of plasma were collected in the mid-morning (0930-1130 hr) when activity in the hypothalamic-pituitary-adrenal axis in the rat and control levels of corticosterone were low and were repeated in the afternoon (1400-1600 hr) when activity in the hypothalamic-pituitary-arenal axis and levels of corticosterone were higher. At small doses (1 mg/kg) buspirone had a greater facilitating effect on the hypothalamic-pituitary-adrenal axis than did diazepam. In addition, buspirone had a greater maximum facilitatory effect (477%) on levels of corticosterone than diazepam (345%). However, buspirone (ED50 = 8.6 mumol/kg) and diazepam (ED50 = 8.7 mumol/kg) were equipotent. Administration of 1 mg/kg of buspirone in the morning increased the combined 1/2 and 1 hr circulating levels of corticosterone 75% above control levels. Diazepam, at 1 mg/kg, did not produce any significant changes in levels of corticosterone. Large doses (10 mg/kg) of buspirone increased morning levels of corticosterone by 328% and diazepam increased levels of corticosterone by 265%. During the afternoon small doses of buspirone or diazepam did not significantly alter levels of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of naloxone on serum corticosterone and gastric lesions in stressed rats

In rats subjected to restraint and exposure to cold, naloxone did not significantly influence the increased serum concentrations of corticosterone or the incidence of stress ulceration, but it significantly reduced the severity of gastric lesions. These findings suggest that endogenous opioids released during stress may contribute to the pathogenesis of stress ulceration. They also support the theory that the adrenocorticosteroids are unimportant aetiological factors in stress ulcer formation.     

Effects of adinazolam on plasma catecholamine, heart rate and blood pressure responses in stressed and non-stressed rats.

Adinazolam (ADI) is a new benzodiazepine with anxiolytic and antidepressant properties. To assess its effects on the acute stress response, rats were given a single intraperitoneal injection of 2.5 or 5.0 mg/kg of ADI and stressed for 1 hr by restraint. Neither dose of ADI had any effect on heart rate, blood pressure or norepinephrine (NE) and epinephrine (EP) in plasma in the resting rats. In the stressed animal, 2.5 and 5.0 mg/kg of ADI did not affect stress-induced increases in heart rate or blood pressure but both significantly reduced the stress-induced increases in plasma NE and EP. During certain stressful experiences in patients with abnormally-increased sympathetic drive, ADI may be therapeutically useful in reducing high levels of catecholamines.     

Effects of diazepam on conflict behaviour and on plasma corticosterone levels in male and female rats

The anxiolytic properties of diazepam and its effects on plasma corticosterone levels were compared in male and female, water deprived rats exposed to the punished (0.8 mA) drinking procedure. The effects of diazepam on unpunished licking, tested under familiar or unfamiliar conditions, and on the lick latency were also studied and a comparison between the two sexes was made. Both punished and unpunished drinking were less in females than in males. In both sexes, a clear anticonflict effect, i.e. a much greater effect on punished than on unpunished drinking, was obtained with 2 and 4 mg/kg, but not with I mg/kg, of diazepam i.p. Plasma corticosterone levels were higher in water deprived females than in males. Following the punished and unpunished drinking procedure, plasma corticosterone levels were found to have decreased more in female than in male rats, especially after administration of 1 mg/kg of diazepam. Diazepam had similar anticonflict effects in rats of both sexes but had a greater suppressive effect on the plasma corticosterone levels in female rats. There was no correlation between the anxiolytic effects of diazepam and its effect on the plasma corticosterone levels. When testing was done under unfamiliar conditions, the latency to licking was greater in female than in male rats and diazepam (1, 2 and 4 mg/kg) increased this latency in both sexes. The results suggest sex differences in the neuroendocrine, but not in the anxiolytic, effects of diazepam.     

Differential effects of ethanol on plasma catecholamine levels in rats

Acute ethanol administration (1-4 g/kg, i.p.) had no effect on plasma catecholamine levels in nonstressed animals except at the highest dose where levels of both catecholamines increased. In animals stressed for 30 min, the higher doses had a biphasic effect on plasma catecholamines; at earlier times during stress a reduction in stress-induced increases in both catecholamines was seen, whereas later during stress or after release from stress an increase was noted. Semi-chronic ethanol administration (0.5 and 2 g/kg/day, i.p.) had no significant effect on plasma catecholamine levels in nonstressed rats. In stressed rats, ethanol reduced stress-induced catecholamine increases but these reductions were less than those seen after acute administration. Although ethanol reduced the gross behavioral stress response, no correlation between gross behavioral and biochemical responses was detected. These data show that ethanol can indeed reduce the behavioral and biochemical stress responses in rats but that effects seen depend on the state (nonstressed vs stressed) of the animal, the dose of ethanol (low vs high) used, the length of ethanol administration (acute vs semi-chronic), and the time of measurement of the catecholamine level after ethanol administration.     

Benzodiazepine receptor antagonists reverse the effect of diazepam on plasma corticosterone in stressed rats

The aim of this work has been to investigate the mechanism by which diazepam counteracts the plasma corticosterone rise induced by stress in rats. This effect is reversed by pretreatment with RO151788 and CGS8216. This observation suggests that the effect is mediated by benzodiazepine-specific receptors in brain.     

Effects of clorgyline and deprenil on corticosterone levels in rats

Adrenal and plasma corticosterone levels were measured in adult female rats after i.p. administration of specific MAO inhibitors: clorgyline (IMAO-A) and deprenil (IMAO-B). Brain and adrenal MAO activity was also determined. The IMAO effect was found to depend on 3 interrelated factors: (a) dose of drug, (b) time after injection, (c) specificity in MAO inhibition. One hour after injection, clorgyline (1 and 2.5 mg/kg) but not deprenil (20 mg/kg), appeared to inhibit the adrenocortical stress response to i.p. injection. At higher doses, MAO-B inhibition by deprenil (40 mg/kg) induced a moderate but sustained increase in corticosterone levels, while MAO-A inhibition by clorgyline (5, 10, 20 mg/kg) resulted in a large and sharp rise. This effect of clorgyline was potentiated with alpha-methyl-p-tyrosine and blocked with p-chlorophenylalanine. On this basis, the involvement of serotonergic mechanisms could be considered to explain the stimulatory effect of clorgyline on adrenal cortical function.     

Pavlovian autoshaping procedures increase plasma corticosterone levels in rats

Pavlovian autoshaping conditioned responses (CRs) are complex sequences of conditioned stimulus (CS)-directed skeletal-motor responses that are elicited by CS objects predictive of food unconditioned stimulus (US). Autoshaping CRs are observed under conditions known to be conducive to elevations in plasma corticosterone levels, as, for example, in response to the eating of food as well as in response to signals predictive of food. Two experiments investigated the relationships between Pavlovian autoshaping procedures, the performance of Pavlovian autoshaping CRs, and plasma corticosterone levels in male Long-Evans rats. In Experiment 1, rats in the CS-US paired group (n=30) were given 20 daily sessions of Pavlovian autoshaping training wherein the insertion of a retractable lever CS was followed by the response-independent presentation of the food US. Tail blood samples obtained after the 20th autoshaping session revealed higher plasma corticosterone levels in the CS-US paired group than in the CS-US random control group (n=10). In Experiment 2, rats (n=35) were assessed for basal plasma corticosterone levels 2 weeks prior to autoshaping training. Plasma samples obtained immediately following the first autoshaping session, and prior to the acquisition of lever-press autoshaping CR performance, revealed higher plasma corticosterone levels in the CS-US paired group (n=24) relative to basal levels. This effect was not observed in the CS-US random control group (n=11). Data suggest that corticosterone release is a physiological endocrine Pavlovian CR induced by lever CS-food US pairings during Pavlovian autoshaping procedures, rather than a by-product of autoshaping CR performance. Implications of the link between autoshaping procedures and corticosterone release are discussed.     

Changes in plasma corticosterone and catecholamine contents induced by low doses of deltamethrin in rats

The effects of low doses of (S)-alpha-cyano-3-phenoxybenzyl (1R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (Roussel UCLAF, Paris, France), (deltamethrin) upon sympathetic-adrenomedullary and pituitary-adrenocortical activity were investigated in rats by measuring plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) concentrations. Blood was sampled from freely-moving animals provided with heart catheters at short intervals up to 60 min after intravenous administration of deltamethrin (0.05, 0.15 and 0.45 mg/kg) or vehicle. Behavioral activity was recorded shortly after the sampling times. Time course and magnitude of the biochemical changes were compared with the effects of exposure to uncontrollable white noise in a similar sampling and recording procedure. Dose-dependent increases were observed for NA and A as well as for CS contents. The dose-response relations however, were different among the neuro-edocrine respondents. Discrete step-wise increases were observed for plasma CS only, indicating greater sensitivity for neurotoxical actions. Already at a dose of 0.15 mg/kg of deltamethrin, CS contents rose to values that were considerably higher than those found during noise exposure. In contrast, plasma CA concentrations increased to noise stress values only after the 0.45 mg/kg dose. The behavioral activity pattern appeared to resemble both CA patterns. The results suggest that rather low doses of deltamethrin elicit vigorous autonomic and neuro-endocrine responses that indicate high levels of stress, presumably caused by the neurotoxic effect of the insecticide.     

Effect of acute ethanol administration on noradrenaline metabolism in brain regions of stressed and nonstressed rats

The effects of ethanol on noradrenaline (NA) metabolism of brain regions in stressed and nonstressed rats were investigated. Male Wistar rats were injected IP with either saline, or ethanol at 0.5 g/kg or 2 g/kg, 5 min before exposure to 1-hr immobilization stress. Levels of NA and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in various brain regions and plasma corticosterone levels were fluorometrically determined. Immobilization stress caused significant increases in MHPG-SO4 levels in all brain regions examined, i.e., the hypothalamus, amygdala, hippocampus, cerebral cortex and locus coeruleus (LC) region. In nonstressed rats, ethanol significantly increased MHPG-SO4 levels in the hypothalamus, hippocampus and cerebral cortex, but not in the amygdala or in the LC region. In stressed rats, ethanol attenuated stress-induced increases in MHPG-SO4 levels preferentially in the amygdala and LC region, but not in the remaining three regions. Although ethanol per se dose-dependently elevated plasma corticosterone levels in nonstressed rats, ethanol at 2 g/kg attenuated the stress-induced elevation of corticosterone. These results suggest that the attenuating effect of ethanol on stress-induced increases in NA turnover in the amygdala and LC region might be related to the stress-relieving properties of this drug.     

Factors influencing plasma catecholamine levels in rats during immobilization

Catheterized young and old male and female rats in estrus and diestrus were immobilized for 30-min periods. Six serial blood samples were drawn over one hour and the plasma was assayed for the catecholamines (CA) norepinephrine (NE) and epinephrine (E). Baseline CA levels were higher in awake young male rats than in asleep males, and still higher in old male rats. Highest basal NE levels were found in diestrus females. Immobilization produced similar elevations in plasma CA for all groups. Peak values occurred at 1–5 min and declined slowly thereafter toward baseline. Repreated stress of young male rats caused habituation as evidenced by diminished peak CA levels during the second and third restraint. Age, time of exposure and day of the cycle in female rats had subtle, though statistically significant, effects on CA levels at various times during and after immobilization and on the total stress response.     

Comparison of noncontingent versus contingent cocaine administration on plasma corticosterone levels in rats

The purpose of the present study was to compare the effects of contingent and noncontingent cocaine administration on plasma levels of corticosterone in rats. Male rats were trained to self-administer cocaine under a fixed-ratio 5 schedule. The rats were yoked such that the delivery of cocaine (0.25 mg/kg/infusion) to one rat (contingent cocaine) produced the simultaneous noncontingent delivery of the same dose of cocaine (noncontingent cocaine) or saline (noncontingent saline) to other rats. Although saline administration had no effect, plasma corticosterone levels were significantly higher in rat receiving contingent cocaine compared to those receiving noncontingent cocaine. These results demonstrate that the active vs. passive administration of cocaine can differentially affect this neuroendocrine response.     

Prenatal stress: Effects on brain biogenic amine and plasma corticosterone levels

Pregnant rats were subjected to once daily stress treatments consisting of handling and a saline injection. The offspring showed region-specific changes in brain 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in infancy but only the hypothalamus still showed significant changes at 60 days of age. In a reaction-to-stress test 23-day-old offspring in the prenatal stress group showed a greater elevation in plasma corticosterone level but smaller changes in hypothalamic NE and 5-HIAA levels than control offspring suggesting that prenatal stress may have altered the functioning of the hypothalamic-pituitary-adrenal axis. It is suggested that changes in the development of specific monoamine-containing neurons may be associated with the reported behavioral deficits in offspring of female rats stressed during pregnancy.     

Effect of diazepam on plasma corticosterone levels

In light of the numerous but rather conflicting reports on the action of benzodiazepines upon the hypothalamo-hypophyseal-adrenal (HHA) axis activity, the effect of different doses of diazepam (0.1, 1.0 and 10.0 mg/kg) administered 15, 30, 60, 120 and 240 min before decapitation on plasma corticosterone level was studied in rats. While 0.1 mg/kg diazepam had no effect, 1.0 mg/kg diazepam decreased plasma corticosterone levels 30 and 60 min following drug administration. On the other hand, treatment with 10.0 mg/kg diazepam produced an increase in plasma corticosterone levels from 15–120 min following drug administration.