Berrilyn J. Branch

Long-term effects of fetal ethanol exposure on pituitary-adrenal response to stress ☆

Pregnant female rats were fed either a 5.0-5.5% w/v ethanol-containing liquid diet ad lib or pair-fed the isocaloric control diet during gestation weeks 2 and 3. At 75-105 days of age, female offspring of the ethanol-treated dams showed significantly greater corticosterone responses than pair-fed- or normally-derived offspring to the stress of cardiac puncture or of noise and shaking, while pituitary-adrenal responses to exposure to a novel environment, cold or 2-3 days of fasting were normal. Adrenal sensitivity to ACTH in dexamethasone-suppressed adult offspring was unaffected by the prenatal treatment. The results demonstrate that fetal ethanol exposure enhances adult pituitary-adrenal responses to certain stressors, including alcohol as demonstrated previously, and suggest that the long-term effects may be mediated by developmental actions of alcohol on central neural mechanisms involved in the regulation of this neuroendocrine system.

Prenatal ethanol and ontogeny of pituitary-adrenal responses to ethanol and morphine

The development of pituitary-adrenal activity was examined in the offspring of rat dams fed a 5.0% w/v ethanol-containing liquid diet or pair-fed an isocaloric diet, as a nutritional control, from day 8 of gestation to parturition. Serum corticosterone responses of the pups to challenges with ethanol (1.5 g/kg) or morphine (3.0 mg/kg) were determined at 5, 7, 10, 12 and 18 days of age. The pituitary-adrenal axis of normal neonates was activated by the drugs at each age, with a characteristic biphasic developmental pattern in which a trough occurred at day 7. The overall pattern was unaffected by prenatal ethanol exposure or pair-feeding. However, both prenatal treatments intensified the trough. Already on day 5 and also on day 7, corticosterone responses of both the ethanol-exposed and pair-fed offspring to ethanol were significantly lower than responses of normal pups. Additionally, on day 7, ethanol-exposed offspring had significantly lower responses to ethanol than pair-fed offspring and significantly lower responses to morphine than normal pups. Thus, both the prenatal ethanol and pair-feeding treatments suppressed pituitary-adrenal responsiveness of 5 and 7 day-old neonates to the drug challenges. This is in marked contrast to our previous findings for adult prenatally ethanol-exposed offspring whose pituitary-adrenal responses to the same drugs, as well as to other stressors, are consistently enhanced in comparison to pair-fed derived rats, whose responses in adulthood no longer differ from normals.

Effects of amygdaloid stimulation on pituitary-adrenal activity in conscious cats.

Summary The role of the amygdala in ACTH release was studied in freely behaving conscious cats with respect to anatomical specificity, the relation of this hypothalamically mediated function to associated behavioral or electrographic effects and negative feedback action of endogenous steroid levels. Facilitation of ACTH release, as determined by changes in plasma levels of cortisol and corticosterone, occurred primarily in response to stimulation of the corticomedial, basal and lateral amygdaloid nuclei; inhibition, primarily upon stimulation of the corticomedial nuclei. The basal nuclear group also exerted differential inhibitory effects on corticosterone, while the major effect of anterior amygdaloid stimulation was no change in both steroids. These facilitatory and inhibitory effects on ACTH release were unrelated to the occurrence of overt behavioral effects and electrical afterdischarges which were generally avoided by the specific use of low stimulus intensities. The direction of the ACTH response was directly related to the existing level of pituitary-adrenal activity. When initial prestimulatory steroid levels were low, stimulation resulted in facilitation of ACTH release; whereas, when initial levels were significantly higher, inhibition or no change occurred in response to stimulation. These results provide information concerning the organization of the amygdala in its role as a modulator of pituitary-adrenal activity.

Maternal Alcohol Consumption and Stress Responsiveness in Offspring

It is now generally acknowledged that pre- and/or postnatal environmental factors, such as stress and drugs, can exert long-lasting neurobehavioral effects in the individual. These factors may influence the development of central regulatory systems by acting directly on the fetal brain or indirectly through changes in the internal environment of the mother and fetus. The Fetal Alcohol Syndrome which has been recognized as a clinical entity for the past 15 years (1) is a case in point. Adverse effects of maternal alcohol consumption during pregnancy on growth and development of the offspring have been well documented in humans and laboratory animals (2). Mental retardation and behavioral deficits, such as hyperactivity, jitteriness, irritability and marked attentional and learning problems, are consistently observed in children who were exposed to alcohol in utero (3).

Effects of maternal ethanol consumption in rats on basal and rhythmic pituitary - adrenal function in neonatal offspring

Neonatal corticoid treatment delays development of the circadian rhythm of plasma corticosterone in rats. We therefore sought to determine whether fetal or neonatal exposure to ethanol, a substance which activates the hypothalamo-pituitary-adrenal axis, produces similar effects. Subjects were the offspring of dams fed a 5.0% w/v ethanol-containing liquid diet or pair-fed an isocaloric control diet during gestation weeks two and three or during postnatal week one. At birth (day 1), the fetal ethanol-exposed pups had significantly higher brain and plasma corticosterone levels than the pair-fed or normal controls; brain and body weights were unaffected. By day 3, brain and plasma corticosterone titers in the fetal ethanol-exposed pups declined to the levels of the pair-fed and normal controls, although brain weights were significantly reduced. Significantly higher p.m. than a.m. levels of plasma corticosterone first occurred on day 18 both in the fetal ethanol-exposed pups and in the pair-fed and normal controls. Thus, despite its causing elevated corticosterone levels at birth, fetal exposure to ethanol did not affect the onset of the pituitary-adrenal circadian rhythm. On the other hand, exposure to ethanol during the first neonatal week delayed the onset of the pituitary-adrenal rhythm from day 18 to day 21. However, even greater delays occurred in the neonatal pair-fed controls, suggesting that the delays following neonatal exposure were due to nutritional deficits rather than to alcohol per se. The developmental and long-term influences of elevated corticoid levels at birth in fetal ethanol-exposed rats on other aspects of pituitary-adrenal function remain to be determined.

Opioid but not nonopioid stress-induced analgesia is enhanced following prenatal exposure to ethanol

Two neurochemically distinct forms of stress-induced analgesia were examined in adult rats following prenatal ethanol exposure. Rats were exposed to ethanol during the last 2 weeks of gestation through a liquid diet presented to the dams. Analgesia testing was conducted when the offspring were 150–210 days of age. Two forms of footshock stress were administered; one that resulted in a naloxone-sensitive (opioid-mediated) analgesia and one that resulted in a naloxone-insensitive (nonopioid) form of analgesia. Rats prenatally exposed to ethanol demonstrated significantly enhanced opioid-mediated analgesia, but unaltered nonpoioid analgesia compared to controls. These results confirm previous findings that prenatal exposure to ethanol leads to long-term alterations in responding to some, but not all forms of stress. The possibility that prenatal exposure to ethanol leads to perturbations in the endogenous opioid systems is discussed.

Prenatal exposure to alcohol enhances thymocyte mitogenic responses postnatally.

Previous studies have shown altered cell-mediated immune responses in animals prenatally exposed to ethanol. The present study was designed to determine the ontogeny of proliferative responses of thymocytes postnatally following prenatal exposure to ethanol. Thymocytes obtained from 44-day old Sprague-Dawley male rats exposed to 5% (w/v) ethanol during the last two weeks of gestation had a significantly greater response to mitogenic stimulation by concanavalin A (Con A, 5.0 micrograms/ml) than controls. A similar trend was observed in rats at postnatal days 30 and 72, but not at day 16. Con A-conditioned thymoblasts from day-44 fetal alcohol-exposed animals were less responsive to further activation by a crude Con A supernatant than controls, but this response normalized by day 72. These findings reveal that the effects of ethanol exposure in utero in male rats include alterations in the development of thymoproliferative responses to mitogen which persist through the peripubertal period and normalize in part by young adulthood.

Morphine Analgesia is potentiated in adult rats prenatally exposed to ethanol

Exposure to inescapable, intermittent footshock elicits an opioid-mediated stress-induced analgesia in rats. We have previously shown that this response is markedly potentiated in adult rats, prenatally exposed to ethanol. To further investigate our hypothesis that endogenous opioid pain-inhibitory systems are modified by prenatal ethanol exposure, we have measured the analgesic response to morphine, in vitro brain opiate receptor binding characteristics, and occupation of brain opiate receptors following systemic administration of morphine. Compared to controls, rats prenatally exposed to ethanol had significantly enhanced morphine analgesia. This enhancement, however, does not appear attributable to changes in number or affinity of mu or delta opiate receptors, or to altered occupation of receptors by morphine.

Evidence for a cholinergic influence on pineal hydroxyindole O-methyltransferase activity with changes in environmental lighting☆

Abstract Hydroxyindole O-methyltransferase (HIOMT) activity of pineals of rats kept in constant light for one week was significantly lower than HIOMT in pineals of rats kept in constant darkness for one week. These inhibitory effects of light on pineal HIOMT have been shown by others to be mediated by the sympathetic nervous system. What factors mediate the facilitatory effects of the absence of light? In order to answer this question we studied the role of the parasympathetic system by giving female rats on constant light, constant dark or normal lighting schedules daily injections of atropine sulfate, atropine methyl bromide or the cholinomimetic, oxotremorine oxalate, with atropine methyl bromide. The peripherally acting parasympathetic effector blocker, atropine methyl bromide, inhibited the high levels of HIOMT in constant darkness, while the cholinomimetic restored HIOMT activity in darkness. Rats on a normal lighting schedule also had significantly higher levels of HIOMT after oxotremorine than after atropine sulfate. These results indicate that cholinergic mechanisms are involved peripherally, perhaps also centrally, in mediating the response of pineal HIOMT in darkness.

Factors influencing pituitary adrenal rhythmicity: its ontogeny and circadian variations in stress responsiveness

Abstract (1) The controlling mechanism for circadian pituitary-adrenal periodicity is clearly of central neural origin. (2) Ontogenetic modification of the pituitary-adrenal rhythm was investigated in order to determine critical periods in development during which the presence of excess ACTH or corticosteroid would affect normal maturation of the rhythm. (3) Neonatal treatment with ACTH on days 7–9 or 17–19, but not at other times postnatally, suppressed the circadian plasma corticosteroid rhythm in adult rats. (4) Treatment with corticosterone on day 18, but not on days 3, 6 or 12, had similar persistent effects. (5) Thus, brief exposure to high circulating levels of ACTH or corticosterone during two critical neonatal periods which correspond to specific stages in the development of hypothalamic and forebrain structures may affect the normal development of central structures involved in circadian regulation. (6) Development of the pituitary-adrenal rhythm in the female rat is closely related to the onset of puberty. When puberty is delayed, i.e. by neonatal implantation of corticosterone or a sham implant on day 4, maturation of the full amplitude of the circadian rhythm is correspondingly delayed. (7) The role of the hippocampus and septum in the circadian periodicity of stress-induced pituitary-adrenal responsiveness was investigated. (8) Electrical stimulation of hippocampus in freely-behaving chronically-implanted adult male rats prolonged the plasma corticosterone response to 10-min restraint stress in the morning, but was without effect in the afternoon. (9) Septal stimulation in the afternoon abolished the plasma corticosterone response to the stress, whereas stimulation in the morning was less effective. (10) These differential effects obtained at the trough and peak of the pituitary-adrenal cycle suggest that hippocampus and septum may play a role in producing the diminished stress responsiveness normally observed at the peak of the cycle.