The effects of adrenalectomy and corticosterone replacement on induction of maternal behavior in the virgin female rat

Maternal behavior of the sensitized virgin rat is affected by approach-avoidance systems as well as by hypothalamic-pituitary-adrenal (HPA) axis, which is also activated during stress. The present experiments investigated the effects of adrenalectomy and of varying corticosterone concentrations on the onset and expression of maternal behavior in sensitized virgin rats. In the first experiment, latency to onset of maternal behavior and time spent licking once maternal were positively related to endogenous levels of corticosterone. However, few rats showed licking. In the second experiment, virgin rats were adrenalectomized or given sham surgeries before being sensitized and being given 0, 25, 100, 300, or 500 microg/mL of corticosterone in their drinking water. In the third experiment, virgin rats were adrenalectomized or given sham surgeries and given either control or corticosterone time-release pellets after being sensitized. Maternal behavior was then tested. Adrenalectomy increased licking in the second experiment and time over pups in the third experiment. Corticosterone replacement reduced licking in the second experiment and both licking and time over pups in the third experiment. In conclusion, exogenous corticosterone had an inhibitory effect on the expression of maternal behavior in the sensitized virgin rat, unlike the facilitatory effect previously found in the postpartum rat.     

The effects of adrenalectomy and corticosterone replacement on maternal memory in postpartum rats

Hormones associated with parturition prime rats to behave maternally, although hormonal changes are not necessary for these behaviors to occur. Experience with pups after birth enhances maternal responsiveness after a period of isolation, creating a maternal memory. The purpose of this study was to determine the role of corticosterone in the formation of maternal memory. Adrenalectomy or sham surgeries were performed in late gestation with corticosterone or vehicle pellets being given to adrenalectomized rats. Pups were removed immediately following parturition, and half of the rats received 4 h of pup experience, while the other half received only brief pup experience associated with parturition. Ten days following pup experience, foster pups were given to all rats. Latency to become maternal and maternal behaviors on the first 2 days of re-exposure and the first two maternal days were recorded. Among adrenalectomized rats given corticosterone, 4-h experience with pups decreased maternal latency when compared to brief experience with pups. This maternal experience effect was not found in comparisons between adrenalectomized rats not given corticosterone. In addition, corticosterone decreased latencies regardless of pup experience. Corticosterone also increased maternal behavior upon initial exposure to foster pups. In conclusion, corticosterone enhanced maternal memory and initial maternal behavior in postpartum rats.     

Adrenalectomy affects pain behavior of rats after formalin injection

Stressful stimuli can activate the hypothalamo-pituitary-adrenal-axis and the endogenous opioid system. In addition, corticosterone and opioid release might cause analgesia. This rat study used adrenalectomy for corticosterone withdrawal and naloxone administration for opioid antagonism in order to study pain behavior and hypophyseal hormone release in the plasma after a formalin test. Twelve days before the formalin testing, male Sprague Dawley rats underwent adrenalectomy or sham-adrenalectomy, and non-operated rats were used as reference. The number of flinches and the duration of licking or biting behavior were measured during the early and late phase. In reference and sham-operated rats, injection of formalin 5% resulted in a marked pain behavior in the early and late phase with significant increases in ACTH and corticosterone plasma levels. In adrenalectomized rats, pain behavior was decreased during both phases. Naloxone, administered before the late phase, did not alter pain behavior in sham or reference rats, whereas in adrenalectomized rats pain reactivity returned to those levels observed in reference rats. Beta-endorphin plasma levels above the detection limit were more frequently found in adrenalectomized rats. Thyrotropin and prolactin levels were not different between studied groups. We speculate that the observed reduced pain behavior in adrenalectomized rats after formalin, is the result of an increased production of pro-opiomelanocortin, the pro-drug of both adrenocorticotrophic hormone and beta-endorphin.     

Effect of the exercise-induced increase in glucocorticoids on endurance in the rat

To investigate the effect of the increase in glucocorticoids during exercise on endurance, rats were either sham operated (SO) or adrenalectomized. All adrenalectomized rats were given a subcutaneously implanted corticosterone pellet at the time of adrenalectomy. Adrenalectomized rats were injected with corticosterone (ADX Cort) or corn oil (ADX) 5 min before exercise. Rats were killed at rest or after running on a treadmill (21 m/min, 15% grade) until exhaustion. SO rats ran 138 +/- 6 min compared with 114 +/- 9 min for ADX Cort and 89 +/- 8 min for ADX. All differences in run times were significant (P less than 0.05). Corticosterone levels were similar in exhausted SO and ADX Cort groups. ADX exhausted rats had corticosterone levels similar to resting values in SO and ADX rats. Inhibition of the rise in glucocorticoids during exercise had no effect on liver glycogen, liver adenosine 3',5'-cyclic monophosphate, plasma insulin, blood glucose, lactate, glycerol, or 3-hydroxybutyrate, plasma norepinephrine, or red quadriceps and soleus glycogen. Plasma free fatty acids were significantly depressed at exhaustion in ADX rats compared with SO. These data show that glucocorticoids exert effects within the time frame of a prolonged exercise bout and play a role in increasing endurance.     

Compensatory gastroprotective action of glucocorticoid hormones in the rats with ablation of capsaicin-sensitive neurons

We tested the hypothesis that contribution of glucocorticoids in gastroprotection become especially important during ablation of capsaicin-sensitive neurons. For this, the effect of desensitization of capsaicin-sensitive neurons on the gastric mucosa was compared in groups of rats with different glucocorticoid supply: sham-operated and adrenalectomized without and with corticosterone replacement (4 mg/kg sc). Functional ablation of capsaicin-sensitive neurons was performed with neurotoxic doses of capsaicin (20 + 30 + 50 mg/kg sc). Indomethacin in the dose 35 mg/kg was given as an ulcerogenic stimulus. It was shown that combination of adrenalectomy with desensitization of capsaicin-sensitive neurons potentiated the effect of sensory desensitization alone on indomethacin-induced gastric erosions. Corticosterone replacement prevented this effect of adrenalectomy. The results suggest a pivotal compensatory role of glucocorticoids in maintenance of gastric mucosal integrity during ablation of caspsaicin-sensitive sensory neurons.     

Corticosterone regulates calbindin-D28k mRNA and protein levels in rat hippocampus

Corticosterone was administered to normal and bilaterally adrenalectomized rats (250-300 g), and hormonal regulation of brain calbindin-D28k (CaBP28k) levels was investigated by radioimmunoassay for CaBP28k protein and by slot and Northern blot analyses for CaBP28k mRNA. The specificity of the changes observed in CaBP28k mRNA levels was tested by reprobing blots with calmodulin and B-actin cDNAs. Rats were either adrenalectomized, adrenalectomized treated with corticosterone, intact, or intact treated with corticosterone. Chronic corticosterone administration (subcutaneous injection for 7 days, 10 mg/day) to normal intact rats significantly increased levels of CaBP28k immunoreactivity (43%) and mRNA (125%) in the hippocampus. Adrenalectomy (animals were killed 7 days after adrenalectomy) produced a significant decrease in hippocampal CaBP28k immunoreactivity (85%) and mRNA (80%) compared with intact controls. Immunocytochemical analysis of tissue sections inducated a marked depletion of CaBP28k immunoreactivity in the dentate gyrus of the hippocampus 2 weeks after adrenalectomy. When adrenalectomized rats were treated with corticosterone (10 mg/day for 7 days), CaBP28k protein and mRNA levels in hippocampus were restored to levels observed in intact controls. No changes in CaBP28k protein and mRNA in kidney, cerebellum, striatum, or cerebral cortex were noted in adrenalectomized rats or in intact rats treated with corticosterone when compared with controls, indicating the specificity of the effect on CaBP28k for the hippocampus. These studies present the first evidence of a regulator of CaBP28k gene expression in the brain.     

Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptors in rats

Our previous investigations suggest that the reduction of stress-induced corticosterone release, or inhibition of corticosterone actions, promotes stress-induced gastric erosions in rats. In this study the effect of glucocorticoid deficiency on susceptibility to gastric mucosal injury by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated in rats. Gastric erosions induced in male rats by indomethacin (25 mg/kg sc) or acidified aspirin (40 mM po) were studied one week after adrenalectomy with or without corticosterone replacement or after occupation of glucocorticoid receptors by the antagonist RU-38486 during the period of erosion formation. Corticosterone for replacement (4 mg/kg sc) was injected 15 min before the administration of indomethacin or acidified aspirin to adrenalectomized rats. The antagonist RU-38486 (10 mg/kg po) was administered twice, 20 min before and 60 min after NSAID administration. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Indomethacin or acidified aspirin induced both plasma corticosterone rise and gastric erosions. Adrenalectomy decreased both basal and NSAID-induced corticosterone levels and markedly promoted gastric erosion formation caused by the NSAID. An acute corticosterone replacement mimicking indomethacin-and aspirin-induced corticosterone rise prevented the effect of adrenalectomy on the gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of gastric erosions induced by indomethacin as well as aspirin. These observations suggest a gastroprotective action of glucocorticoids released in response to NSAID treatment against NSAID-induced injury.     

Adrenalectomy in genetically obese ob/ob and db/db mice increases the proton conductance pathway

Adrenalectomy (ADX) prevents the excessive weight gain in the genetically obese ob/ob and db/db mice. To test the possibility that this results from increased energy expenditure due to increased thermogenesis in brown adipose tissue (BAT), we measured GDP binding to mitochondria from interscapular brown adipose tissue (BAT) in db/db and ob/ob mice and their lean controls after adrenalectomy, with and without corticosterone replacement. Both the vehicle treated and corticosterone treated db/db and ob/ob mice had lower body weights than the sham-operated mice GDP binding to mitochondria from IBAT was significantly lower in both the db/db and ob/ob mice than in their lean controls. Adrenalectomy significantly increased GDP binding in all mice compared to the respective sham-operated mice, but, the percentage increase was always greater in the db/db and ob/ob mice. Corticosterone treatment of adrenalectomized db/db, ob/ob or lean mice lowered GDP binding to sham levels. Our data confirm previous findings that adrenalectomy results in increased GDP binding to mitochondria from IBAT. Injections of corticosterone into adrenalectomized mice results in a decrease in GDP binding to values which are similar to values in sham-operated mice. Thus adrenalectomy may inhibit the development of obesity by increasing the thermic activity in IBAT.     

Persistent pain responses under inflammation and corticosterone levels in juvenile rats born to adrenalectomized dams

Juvenile Wistar rats born to dams adrenalectomized 34 weeks before mating were used to study the intensity of indices of behavioural pain responses (number of flexing + shaking and duration of licking patterns) produced by inflammation in the formation test as well as plasma corticosterone levels during the pain response. It has been found that dams' adrenalectomy does not change either basal corticosterone levels or the indices of pain response intensity. During persistent pain (25 min after the formation injection), corticosterone levels were enhanced reliably (p < 0.05) in offspring of both intact and adrenalectomized dams. Females born to adrenalectomized dams showed the higher corticosterone levels (p = 0.008) as a response to persistent pain as compared to those born to sham-operated dams. No differences in pain indices in female offspring of adrenalectomized and sham dams were revealed. There were no sex differences in the indices of pain response and corticosterone. Thus, the pain evoked by inflammation in the formalin test has an activating effect on the hypothalamo-hypophyseal-adrenocortical system in 25-day-old pups, but the released corticosterone fails to reduce pain intensity in the formalin test as evidenced by data obtained in offspring of adrenalectomized dams.     

Effect of corticosterone on the prolactin response to psychological and physical stress in rats

Both corticosterone and prolactin (PRL) levels increase in response to stress. In these studies we examined the effect of corticosterone on the PRL response to both physical (footshock) and psychological (novel environment) stress. Three groups of rats were used: sham adrenalectomized (SHAM), adrenalectomized (ADX), and adrenalectomized with corticosterone replacement (ADX+CORT). The corticosterone-treated animals received 80 ug corticosterone/ml drinking water. Blood samples were drawn via an indwelling cannula and PRL values determined using radioimmunoassay. ADX rats showed a consistently greater PRL response to being placed on a platform above water (novel environment) or when receiving intermittant footshock than did ADX+CORT rats. The PRL response of the latter group was similar to that of the SHAM animals. These findings indicate that corticosterone levels of an animal can significantly attenuate the magnitude of the PRL response to both physical and psychological stress. These findings further emphasize that the PRL response to stress is dependent not only upon the immediate action of the stressor, but also the prior stress history of the animal.     

Effect of glucocorticoid administration on the rate of muscle protein breakdown in vivo in rats, as measured by urinary excretion of Nτ-methylhistidine

The role of glucocorticoids in regulating the rate of muscle protein breakdown was evaluated by measuring excretion of N(tau)-methylhistidine during administration of various doses of corticosterone to adrenalectomized rats. Groups of rats received daily subcutaneous injections of 0, 0.2, 0.5, 1.0, 5.0 or 10.0mg of corticosterone/day per 100g body wt. for 7 days, followed by 3 days without hormone treatment, after which they were killed. A group with intact adrenal glands served as an additional control. All animals were pair-fed with the untreated adrenalectomized group. No significant differences were noted in growth rate or N(tau)-methylhistidine excretion between the intact or adrenalectomized control groups, or those given 0.2, 0.5 and 1.0mg of corticosterone, whereas growth ceased and N(tau)-methylhistidine excretion rose markedly in the groups receiving 5 and 10mg of corticosterone. After these two high doses of corticosterone, but not after lower doses, there was a loss of weight of the gastrocnemius muscle per 100g of final body wt., but not of the soleus and extensor digitorum longus muscles. The two highest doses of corticosterone also resulted in an increase in liver weight per 100g of final body wt. Lower doses of corticosterone did not cause these changes. Plasma corticosterone concentrations, measured on the final day of injection and again at the time of killing, were decreased to near zero by adrenalectomy and were little raised by doses of 0.2 and 0.5mg daily, but were increased to within the normal range by the 1mg dose. At 5 and 10mg doses, plasma corticosterone concentrations were sustained at 2-3 times those of intact rats, and thus in the range reported for rats exposed to severe stress. Rats given 5 and 10mg doses of corticosterone had glycosuria, and showed considerably elevated concentrations of insulin in the plasma. It is concluded that plasma concentrations of glucocorticoids within the normal range do not regulate the rate of muscle protein breakdown, whereas excessive plasma concentrations of corticosteroids, equivalent to those observed in severe stress, can accelerate muscle protein breakdown.     

Adrenal steroids and extinction behavior: Antagonism by progesterone,deoxycorticosterone and dexamethasone of a specific effect of corticosterone

Extinction behavior was nearly absent in rats adrenalectomized one hour prior to forced extinction of a passive avoidance response. A low dose of corticosterone administered immediately after adrenalectomy normalized extinction behavior. Progesterone, 11-deoxycorticosterone and the synthetic glucocorticoid dexamethasone were not effective at the same or ten times higher doses. Instead, pre-treatment with these steroids prevented the normalizing effect of corticosterone on extinction behavior. These characteristics of steroid effects on behavior correspond to the strict specificity of the corticosterone receptor system in hippocampal neurons. The agonist or antagonist interaction of naturally occurring adrenal steroids with brain cells may serve behavioral adaptation.     

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.     

Adrenal modulation of the inhibitory effect of corticotropin releasing factor on feeding

Corticotropin releasing factor (CRF) reduces food intake in rats after central administration. In these studies we examined whether the adrenal gland and the vagus were involved in CRF suppression of intake. One hour intake was reduced by a 5 μg (ICV) injection of CRF in sham but not adrenalectomized rats maintained on 0.9% NaCl. In a separate experiment on rats maintained on tap water, the inhibitory effect of CRF (5 μg) lasted at least 4 hours in sham rats whereas adrenalectomized rats did not significantly differ from controls. These experiments suggest that the adrenal gland modulates the feeding response to CRF. As replacement with corticosterone (0.75 mg/kg) in total adrenalectomized rats did not restore responsiveness to 5 or 10 μg of CRF, we next studied whether the adrenal medulla was responsible for the decreased responsiveness to CRF. In rats lacking the adrenal medulla only, food intake was reduced by a 5 μg injection of CRF; in sham rats, intake was significantly reduced by doses as low as 0.1 μg of CRF. An additional experiment examined the effect of gastric vagotomy on the CRF feeding response. Vagotomized rats were as responsive to 5 and 10 μg injections of CRF as sham rats, which suggests that the effect is not dependent on the vagus nerve. These findings indicate that the adrenal gland, primarily the medulla, plays an intermediate role in the reduction of food intake caused by central injections of CRF. This conclusion is consistent with the known effect of CRF on adrenomedullary discharge.     

Parity-associated reductions in behavioral sensitivity to opiates

Behavioral and physiological responses differ between primiparous and multiparous female rodents. Specifically, multiparous females respond with the full repertoire of maternal behaviors much more rapidly and with greater intensity than their primiparous counterparts. Since opiates inhibit the expression of maternal behavior in postpartum rats and can be reversed by means of the opiate antagonist naloxone, we investigated whether multiparous females would be resistant to the inhibitory effects of opiates on maternal behavior, relative to primiparous females. In Experiment 1 we evaluated the effects of a range of doses of morphine sulfate (MS; 0.625, 1.25, 2.5, 5.0, and 10.0 mg/kg or saline) on maternal behavior in primiparous females on Days 5-6 of lactation. The 5.0 and 10.0 mg/kg doses effectively disrupted maternal behavior, whereas the lower doses were ineffective or only marginally disruptive. In Experiment 2, age-matched female rats were timed-mated and tested for maternal behavior from Day 5 to 13 of lactation, after daily injections of the 5.0 mg/kg dose of MS. On Day 5 of lactation, this morphine treatment eliminated full maternal behavior in 87% of the primiparous animals, but only 37% of the multiparous animals were affected. By Day 10 of lactation, 100% of the multiparous females displayed full maternal behavior after MS treatment, whereas only 69% of primiparous females were responsive. In Experiment 3, analgesic responses were measured both in rats experiencing their initial or second pregnancy, and in postpartum, lactating rats after MS (5.0 mg/kg) administration. Using a tail-flick apparatus to measure analgesia, we found multigravid females to be significantly less analgesic prepartum than primigravid females, suggesting less sensitivity to endogenous opioids.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenalectomy does not prevent the hyperprolactinemic, induced sexual behavior deficits in CDF male rats

Inbred male CDF rats were bilaterally adrenalectomized and received either two pituitaries under each kidney capsule or were sham operated. They were tested at approximately four, seven and eight weeks after surgery. Between the first and second behavioral test, the animals received corticosterone replacement therapy. In each of the three tests, grafted animals exhibited deficits in male sexual behavior as compared to sham-grafted controls. These results suggest that, at least in CDF inbred rats, the adrenal gland is not necessary for the reduction in male sex behavior resulting from chronic hyperprolactinemia.     

Glucocorticoids impair fetal beta-cell development in rats

In rats, poor fetal growth due to maternal food restriction during pregnancy is associated with decreased beta-cell mass at birth and glucose intolerance in adulthood. Overexposure to glucocorticoids in utero can induce intrauterine growth retardation in humans and animals and subsequent glucose intolerance in rodents. The aims of this study were to investigate whether glucocorticoid overexposure mediates the effect of undernutrition on beta-cell mass and to study their potential role in normally nourished rats. Undernutrition significantly increased maternal and fetal corticosterone levels. Twenty-one-day-old fetuses with undernutrition showed growth retardation and decreased pancreatic insulin content; adrenalectomy and subcutaneous corticosterone implants in their dams prevented the maternal corticosterone increase and restored fetal beta-cell mass. In fetuses with normal nutrition, fetal corticosterone levels were negatively correlated to fetal weight and insulin content; fetal beta-cell mass increased from 355 +/- 48 microg in sham to 516 +/- 160 microg after maternal adrenalectomy; inhibition of steroid production by metyrapone induced a further increase to 757 +/- 125 microg. Our data support the new concept of a negative role of glucocorticoids in fetal beta-cell development.     

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats

We investigated the mechanisms underlying the protective action of glucocorticoids against indomethacin-induced gastric lesions. One-week adrenalectomized rats with or without corticosterone replacement (4 mg/kg sc) were administered indomethacin (25 mg/kg sc), and gastric secretion (acid, pepsin, and mucus), motility, microvascular permeability, and blood glucose levels were examined. Indomethacin caused gastric lesions in sham-operated rats, with an increase in gastric motility and microvascular permeability as well as a decrease in mucus secretion. Adrenalectomy significantly worsened the lesions and potentiated these functional disorders. Glucose levels were lowered by indomethacin in sham-operated rats, and this response was enhanced by adrenalectomy. The changes observed in adrenalectomized rats were prevented by supplementations of corticosterone at a dose mimicking the indomethacin-induced rise in corticosterone, whereas the protective effect of corticosterone was attenuated by RU-38486, a glucocorticoid receptor antagonist. We conclude that the gastroprotective action of endogenous glucocorticoids may be provided by their support of glucose homeostasis and inhibitory effects on enhanced gastric motility and microvascular permeability as well as maintaining the production of mucus.