Prenatal ethanol exposure permanently reduces the number of pyramidal neurons in rat hippocampus

Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism.

The detrimental effects of maternal drinking during pregnancy on fetal health have been documented. The consequences for infants of maternal drinking during breast-feeding are unknown, but research in animals suggests that the infant could be affected by exposure to alcohol through the mother's milk. In a study of 400 infants born to members of a health maintenance organization, we investigated the relation of the mother's use of alcohol during breast-feeding to the infant's development at one year of age. Mental development, as measured by the Bayley Mental Development Index (MDI), was unrelated to maternal drinking during breast-feeding. However, motor development, as measured by the Psychomotor Development Index (PDI), was significantly lower in infants exposed regularly to alcohol in breast milk (after alcohol exposure during gestation was controlled for), with a dose-response relation (P for linear trend, 0.006). The infants of breast-feeding mothers who had at least one drink daily had a mean PDI score of 98, whereas the infants exposed to less alcohol in breast milk had a mean PDI score of 103 (95 percent confidence interval for the difference of the two means, 1.2 to 9.8). The effect was more pronounced when mothers who supplemented breast-feeding with formula were excluded from the analysis. The association persisted even after we controlled for more than 100 potentially confounding variables, including smoking and other drug use during pregnancy and in the postpartum period. We conclude that ethanol ingested through breast milk has a slight but significant detrimental effect on motor development, but not mental development, in breast-fed infants.

Maternal Alcohol Use during Breast-Feeding and Infant Mental and Motor Development at One Year

This review discusses some of the mechanisms through which alcohol (EtOH) alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis. In adult rats, acute EtOH treatment increases plasma ACTH and corticosteroids levels primarily by stimulating the release of corticotropin-releasing factor (CRF) and possibly vasopressin (VP) from nerve terminals in the median eminence. Increased CRF gene transcription in the hypothalamus may also be important. The HPA axis remains activated during chronic EtOH exposure, although habituation may take place. Changes in the responsiveness of hypothalamic neurons, a phenomenon itself dependent in part on a number of intermediate secretagogues, as well as decreased pituitary responsiveness to VP, all play a role. Finally, the activity of the HPA axis is influenced by exposure to EtOH during embryonic development, with mature offspring showing hyporesponsiveness to many stimuli. These altered responses appear to be caused in part by changes in the synthesis/release CRF, possibly under the influence of nitric oxide. CRF, VP, ACTH, and corticosteroids are important regulators of the immune system, behavior, metabolic pathways, and reproductive parameters. Alcohol therefore may influence such functions through the pathological secretion of these hormones. A better understanding of the mechanisms through which the drug alters their release thus may permit the development of therapies designed to alleviate some of the consequences of alcoholism.

Alcohol stimulates ACTH secretion in the rat: mechanisms of action and interactions with other stimuli.

Critical periods for ethanol-induced cell loss in the hippocampal formation.

The effects of ethanol on the physical development and maturation of the CNS in the offspring of lactating rats were investigated. Dams were fed: 1) regular stock diet (control), 2) liquid diet containing 35% of the calories as ethanol (ETOH) or 3) liquid diet with maltose-dextrin substituted for the calories supplied by ethanol (isoenergetic = IE). Diets were administered from the 14th day of gestation until 3 weeks post-partum (pre- and post-natal exposure) or from birth until 3 weeks post-partum (post-natal exposure). Body weight, crown-rump length and tail length, as well as brain weight were followed longitudinally in the pups. The growth in the pups of dams fed ETOH diet and those fed IE diet were significantly less than that observed in the pups of control dams. Furthermore, pups of dams fed the ETOH diet showed retardation in growth indices and brain weight at various ages when compared to pups of equivalent age from dams fed the IE diet. Therefore, administration of ethanol to pregnant or lactating dams impaired the physical growth, including central nervous systems (CNS), of their offspring more than those changes caused by nitritional deprivation.

The Effects of Maternal Ethanol Consumption in the Rat on the Development of their Offspring

The comparative effects of exposure to ethanol and malnutrition on the concentrations of tyrosine and catecholamines in whole brain and selected regions of brain have been studied in the developing rat. These animals were the offspring of optimally nourished rats (control pups), of rats fed a diet with 35% of the calories supplied by ethanol (ETOH pups), or of animals fed a diet calorically equivalent to the latter but lacking ethanol (iso-caloric, 1C pups). These diets were administered to dams either during the last week of gestation (prenatal) or during lactation (postnatal). Tyrosine levels were elevated prior to birth in the prenatal ETOH or IC pups or at 1 and 2 weeks of age in postnatal ETOH or 1C pups as compared with values found in the control offspring. Dopamine concentration in whole brain was significantly lower in prenatal ETOH pups than in prenatal IC pups at 3 weeks of age. Levels in the brains of postnatal ETOH pups were lower than control values, but not relative to animals exposed to 1C diet. Investigation of corpus striatum showed a significant decrease in dopamine concentration compared with control or IC pup values as a result of postnatal exposure to ethanol. Norepinephrine levels in the whole brain of prenatal ETOH pups were consistently 30–40% lower than either control or matched 1C pups during development. At 3 weeks of age, the norepinephrine levels in the hypothalamus of animals exposed to ethanol pre or postnatally were 30–60% lower than values in the corresponding region in either control or 1C pups. In the rat model described, ethanol caused a decrease in catecholamine levels, perhaps solely by affecting the norepinephrine neurons.

Comparative Effects of Ethanol and Malnutrition on the Development of Catecholamine Neurons: Changes in Neurotransmitter Levels

Exposure to ethanol during only the last week of gestation in the rat resulted in significantly decreased weight and levels of norepinephrine in the hypothalamus of the offspring after 26 weeks on standard diet compared with appropriate controls.

Comparative Effects of Ethanol and Malnutrition on the Development of Catecholamine Neurons: A Long-Lasting Effect in the Hypothalamus



A rat model was developed in which the comparative effects of malnutrition and ethanol on the neurochemical maturation of catecholamine neurons in brain were studied. The animals were offspring of rats optimally nourished (control pups), fed a diet with 35% of the calories supplied by ethanol (EtOH pups), or a diet calorically equivalent to the latter but lacking ethanol (isocaloric = IC pups). These latter two groups were calorically deprived since rats fed the diet containing ethanol ate 40–60% less than the optimally nourished group. The diets were administered to dams either during the last week of gestation (prenatal) or during lactation (postnatal). The protein content per gram wet weight was not significantly different between brains of control and experimental pups. Developmental changes in EtOH pups were noted in the activities of tyrosine hydroxylase (TOH) and dopamine β-hydroxylase (DBH). The specific activity of TOH was increased in EtOH and IC pups preand postnatally. In the postnatal experimental group TOH activity in the brains of EtOH pups was higher not only when compared with control pups but also with IC pups. Prenatal caloric deprivation or ethanol exposure also caused increased specific activity of DBH in the neonatal rat brain. In contrast, exposure to ethanol postnatally caused a significant and persistent reduction in the specific activity of DBH, not only compared with control pups but also to matched IC pups exposed postnatally to the IC diet. The specific activity of 3,4-dihydroxyphenylalaninedecarboxylase (DOPADC) was significantly elevated in the brains of prenatal and postnatal EtOH and IC pups, with little difference between the groups. Activities of monoamine oxidase (MAO) or catecholamine-0-methyltransferase (COMT) were generally lower in EtOH or IC pups than in control pups, again with little difference between EtOH and IC pups. These results suggest that an impaired metabolism of dopamine and norepinephrine is detectable in the brains of pups as a consequence of malnutrition, ethanol exposure, or both.

Comparative effects of ethanol and malnutrition on the development of catecholamine neurons: changes in specific activities of enzymes.

A persistent and significant decrease in the concentration of norepinephrine in whole brain and hypothalamus was observed in 1-21-day-old rats exposed to ethanol preor postnatally (Detering e t al., 1980b). The studies reported here were carried out in an attempt to find out whether the decreased levels of norepinephrine in brain were related t o a decreased rate of its synthesis or an increased rate of re lease and removal. The rate of norepinephrine turnover was also measured in the h y p o t h a l a m u s , a r e g i o n w i t h p a r t i c u l a r l y a c t i v e norepinephrine metabolism (Glowinski and Iversen, 1966).

A. Karahasan

Papers

The Effects of Maternal Ethanol Consumption in the Rat on the Development of their Offspring

Comparative Effects of Ethanol and Malnutrition on the Development of Catecholamine Neurons: Changes in Neurotransmitter Levels

Comparative Effects of Ethanol and Malnutrition on the Development of Catecholamine Neurons: A Long-Lasting Effect in the Hypothalamus

Comparative effects of ethanol and malnutrition on the development of catecholamine neurons: changes in specific activities of enzymes.

Comparative effects of ethanol and malnutrition on the development of catecholamine neurons: changes in norepinephrine turnover.