Robert F. McGivern

Androgen regulation of adrenocorticotropin and corticosterone secretion in the male rat following novelty and foot shock stressors

To examine mechanisms responsible for sex differences in hypothalamo-pituitary-adrenal (HPA) axis responsiveness to stress, we studied the role of androgens in the regulation of the adrenocorticotropin (ACTH) and corticosterone (CORT) responses to foot shock and novelty stressors in gonadectomized (GDX) or intact male F344 rats. Foot shock or exposure to a novel open field increased plasma ACTH and CORT, which was significantly greater in GDX vs. intacts. Testosterone (T) or dihydrotestosterone propionate (DHT) treatment of GDX animals returned poststress levels of ACTH and CORT to intact levels. Estrogen treatment of GDX males further increased poststress CORT secretion above GDX levels. There was no difference in the ACTH response of anterior pituitaries from intact, GDX, and GDX+DHT animals to CRF using an in vitro perifusion system. There were no differences in beta max or binding affinity of type I or II CORT receptors in the hypothalamus or hippocampus of intact, GDX, or GDX+DHT groups. These data demonstrate an effect of GDX on hormonal indices of stress. The increased response in GDX rats appears to be due to the release from androgen receptor mediated inhibition of the HPA axis. This inhibition by androgen is not due to changes in anterior pituitary sensitivity to CRH, nor to changes in type I or type II corticosteroid receptor concentrations.

Fast Glucocorticoid Feedback Inhibition of ACTH Secretion in the Ovariectomized Rat: Effect of Chronic Estrogen and Progesterone

The purpose of this study was to determine whether estrogen and progesterone influence fast glucocorticoid negative feedback regulation of the ACTH and corticosterone (CORT) responses to stress. Mature rats were ovariectomized and 6 weeks later implanted with 17 beta-estradiol (E2, 0.5 mg), E2 and progesterone (P, 100 mg; E2 + P group) or placebo pellets (OVX). Seven days later rats were subjected to a single or repeated intermittent footshock stress (0.2 mA, 15 s duration, 0.5 s on). The repeated stress was of the same intensity and duration, and was applied either during the time domain of the rate-sensitive fast glucocorticoid feedback when plasma CORT levels are rising (5 min after the onset of the first stress), or at the time of peak CORT response (15 min) to the initial stress. Plasma ACTH and CORT were measured from serial samples. Estrogen replacement alone or in combination with progesterone lowered the immediate (t = 5) ACTH and CORT response to a single stress in ovariectomized animals. The second stress applied 5 min after the initial stress produced net ACTH responses similar to those obtained after a single stress in the OVX and E2 + P-replaced hormone groups, while total ACTH responses were lower in the E2-treated group. In ovariectomized animals, a facilitation of ACTH response by a prior stress is apparent in response to a footshock 15 min later, when the integrated ACTH secretion is significantly greater than the response measured after a single shock, or after a repeated shock 5 min apart. Anterior pituitary proopiomelanocortin (POMC) mRNA levels were lower in groups with E2 or E2 + P replacement compared to OVX animals. In contrast, hypothalamic corticotropin-releasing factor (CRF) mRNA levels did not increase significantly. However, hypothalamic glucocorticoid receptor (GR) mRNA levels increased after 17 beta-estradiol treatment, and this increase was reversed by progesterone. These results suggest that prior stress leads to both a fast-feedback inhibition and a facilitation of the subsequent stress response. In the absence of gonadal hormones this facilitation is balanced by fast-feedback inhibition during the glucocorticoid fast-feedback time domain, and is unmasked outside of this time domain. Estrogen suppresses POMC mRNA synthesis leading to a decrease in the availability of releasable ACTH, thereby reducing the facilitation. Progesterone may counter this effect of estrogen by decreasing the efficacy of the fast rate-sensitive glucocorticoid negative feedback.

Sex Differences in Visual Recognition Memory: Support for a Sex-Related Difference in Attention in Adults and Children

The selectivity hypothesis of Meyers-Levy (1989) proposes that cognitive sex differences reflect underlying differences in information processing between males and females. Males are considered to be more likely to organize information in a self-related manner, whereas females are more likely to adopt a comprehensive approach to information processing. We tested this hypothesis in children (10-15 years) and adults using recognition memory tasks. Tests were devised which employed male-oriented objects, female oriented objects, or random objects. In both the child and adult samples, females performed significantly better than males on tests using random and female-oriented objects. Males performed at the level of females only when tested for recognition of male-oriented objects. These results demonstrate that this sex difference is present prior to puberty and support the concept of sex differences in information processing.

Behavioral sequelae in young rats of acute intermittent antenatal hypoxia

Several studies have examined behavioral sequelae of acute or chronic pre- or postnatal hypoxia. However, few of these tested a large battery of behavioral functions, particularly those following relatively mild, intermittent hypoxia. Also, in few studies were the hypoxic pups cross-fostered or the experimenter blinded as to experimental group. In addition, in almost no studies were concomitant hypoxic-induced brain biochemicals measured. The present study tested the hypotheses that mild, intermittent antenatal hypoxia can lead to long-term alterations in neurobehavioral development, as well as neurochemical changes.

Prenatal inhibition of hypothalamic sex steroid uptake by cocaine: effects on neurobehavioral sexual differentiation in male rats

Several adrenergically active drugs have been shown to prevent the masculinizing and/or defeminizing effects of testosterone on brain sexual differentiation. We examined the ability of the neuronal norepinephrine uptake blocker, cocaine, to produce similar effects. The ability of cocaine to inhibit sex steroid incorporation into the hypothalamus during a critical period for sexual differentiation of the brain was examined in females treated at birth with testosterone. Sixty minutes after administration, cocaine was observed to inhibit both testosterone and estradiol incorporation into the hypothalamus by approximately 50%. Long-term consequences of prenatal cocaine exposure were studied by injecting Sprague-Dawley dams twice daily with 3, 10 or 30 mg/kg of cocaine hydrochloride on days 15 through 20 of gestation and examining the offspring. In adulthood, cocaine-exposed males, but not females were found to exhibit significantly less marking behavior than controls. Cocaine-exposed males in the 10 mg/kg group tested for sex behavior exhibited demasculinization in some aspects of the behaviors tested. Measurement of plasma hormone levels in this group revealed elevated levels of plasma LH, but normal levels of FSH and testosterone. No differences were observed in cocaine-exposed males with respect to sex organ or adrenal weights, but thymus was approximately 25% smaller compared to control males at 80 days of age. In a separate experiment, dams were treated with 3 mg/kg of cocaine twice daily from days 15 through 21 of gestation and half of the male pups received additional injections twice a day for the first 5 days postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)

Gender differences in incidental learning and visual recognition memory: support for a sex difference in unconscious environmental awareness

Abstract Visual recognition memory is better for familiar objects in adult women compared with men. The present experiments examined whether this gender difference is related to either the greater verbal ability in the female population or greater compliance by females with the task instructions. The role of verbal mediation was studied in 246 undergraduates using recognition memory tasks for both abstract and nameable objects. Females recognized significantly more abstract shapes and nameable objects than males, indicating that the greater recognition memory in females is not dependent upon linguistic mediation. The role of compliance was addressed by examining the performance of 105 undergraduates on an incidental learning task which tested recognition memory for nameable objects. For 60 s, subjects located a star on a computer screen that appeared in different locations against a background of common objects. Immediately following, the subjects were shown a screen on which all of the original objects appeared as well as additional objects. Females identified significantly more objects than males. Together data from these studies suggest that the gender difference in recognition memory reflects a greater unconscious processing of environmental stimuli in females. Results are discussed with respect to the possible role of evolutionary selection with respect to the environmental awareness necessary for care of altricial offspring.

Delayed onset of puberty and subtle alterations in GnRH neuronal morphology in female rats exposed prenatally to ethanol

Fetal alcohol exposed (FAE) animals exhibit physiological and behavioral deficits associated with reproduction including alterations in LH secretion and decreased sex behavior. Such deficits led us to examine the morphological characteristics and number of GnRH neurons in female rats prenatally exposed to ethanol. Sprague-Dawley dams (Harlan, Indianapolis, IN) were administered a fortified liquid diet (Sustacal) containing 35% ethanol derived calories from day 7 through parturition. Controls were pair-fed a similar isocaloric diet containing no ethanol during this period or allowed access to dry food pellets ad lib. Compared to both control groups, puberty was found to be significantly delayed in females that were exposed prenatally to ethanol. The median age of vaginal opening for chow-fed and pair-fed controls was 34-35 days compared to 38-39 days for FAE animals. A subgroup of these females was selected at 44 days of age on the basis of delayed onset of puberty and compared with pair-fed controls for the number and morphology of GnRH-immunoreactive staining (ir) neurons in the medial preoptic area (MPOA) and the diagonal band of Broca (DBB), regions which contain the majority of GnRH-IR cells in the rat brain. In both areas, light microscopic study revealed no differences in GnRH-IR cell number, nor were differences detected among the groups in the number of bipolar versus unipolar cells. However, a significant increase was observed in FAE brains compared to controls in the ratio of GnRH-IR neurons with irregular processes compared to smooth cell contours.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of two weeks versus one week of prenatal ethanol exposure in the rat on gonadal organ weights, sperm count, and onset of puberty

Sprague-Dawley dams from Harlan Ind. (Indianapolis, IN) were administered a fortified ethanol liquid diet containing 35% ethanol derived calories for two weeks (E-2) beginning on day 7 or one week (E-1) beginning on day 13 of gestation and continuing through parturition. Control dams were pair-fed an isocaloric liquid diet containing no ethanol during these periods or remained on lab chow and water. E-2 dams consumed an average of 13.52 g ethanol/kg bwt during the first week of exposure (days 8-14) and 12.50 g ethanol/kg bwt the second week (days 14-20). E-1 dams consumed significantly less than E-2 dams during the second week (9.75 g/kg; p < 0.0001). Although the lower consumption in E-1 dams led to a significant decrease in maternal weight gained during the few days of pregnancy compared to E-2 dams, birthweights of E-1 offspring were significantly heavier than those of E-2 offspring (p < 0.05). No effect of ethanol was detected on anogenital distance at birth in either sex. Puberty was delayed in female offspring of both E-1 and E-2 dams (p < 0.01) as measured by age of vaginal opening. These data suggest that the primary teratogenic actions of ethanol in the rat on fetal growth, as well as delayed puberty in females, occur in the last week of gestation. In adult E-2 males, testis weight was significantly heavier than all other groups when indexed to body weight. No effect of prenatal ethanol exposure was observed on the indexed weights of prostate, epididymis, or seminal vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen receptor β and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats.

The hypothalamic-pituitary-adrenal (HPA) axis is activated in response to stressors and is controlled by neurons residing in the paraventricular nucleus of the hypothalamus (PVN). Although gonadal steroid hormones can influence HPA reactivity to stressors, the exact mechanism of action is not fully understood. It is known, however, that estrogen receptor β (ERβ) inhibits HPA reactivity and decreases anxiety-like behavior in rodents. Since ERβ is co-expressed with oxytocin (OT) in neurons of the PVN, an ERβ-selective agonist was utilized to test the whether ERβ decreases stress-induced HPA reactivity and anxiety-like behaviors via an OTergic pathway. Adult gonadectomized male and female rats were administered diarylpropionitrile, or vehicle, peripherally for 5days. When tested for anxiety-like behavior on the elevated plus maze (EPM), diarylpropionitrile-treated males and females significantly increased time on the open arm of the EPM compared to vehicle controls indicating that ERβ reduces anxiety-like behaviors. One week after behavioral evaluation, rats were subjected to a 20minute restraint stress. Treatment with diarylpropionitrile reduced CORT and ACTH responses in both males and females. Subsequently, another group of animals was implanted with cannulae directed at the lateral ventricle. One week later, rats underwent the same protocol as above but with the additional treatment of intracerebroventricular infusion with an OT antagonist (des Gly-NH2 d(CH2)5 [Tyr(Me)(2), Thr(4)] OVT) or VEH, 20min prior to behavioral evaluation. OT antagonist treatment blocked the effects of diarylpropionitrile on the display of anxiety-like behaviors and plasma CORT levels. These data indicate that ERβ and OT interact to modulate the HPA reactivity and the display of anxiety-like behaviors.

Sex difference in daily water consumption of rats: Effect of housing and hormones

Females rats consume more water than males per day when consumption is indexed to body weight. We examined the developmental expression of this sex difference as well as the organizational and activational influences of testosterone (T). The amount of water consumed from weaning to adulthood exhibited a linear decrease with age in both sexes. The development of a sex difference in water consumption was evident immediately after weaning in singly housed animals, but did not emerge until about Day 42-45 in group-housed animals, when females began to consume greater amounts of water than males. Castration at weaning had minimal effects on the sex difference. Treating dams with testosterone propionate (TP; 0.3 mg/kg; E15-E20) resulted in a significant increase in adult water consumption in offspring of both sexes, but the sex difference remained. Overall, these data indicate that gonadal steroids are not the primary organizational influence on this sex difference. The greater water consumption in females is consistent with other studies demonstrating sex differences in plasma vasopressin levels, as well as differences in vasopressin sensitivity.