Barbaccia Maria Luisa, Scaccianoce Sergio, Del Bianco Paola, Campolongo Patrizia, Trezza Viviana, Tattoli Maria, Cuomo Vincenzo, Steardo Luca
Department of Neuroscience, University of Rome Tor Vergata Medical School, Via Montpellier 1, 00133 Rome, Italy.
Psychoneuroendocrinology. 2007 Sep-Nov;32(8-10):931-42. doi: 10.1016/j.psyneuen.2007.06.013. Epub 2007 Aug 3.
Epidemiological evidence suggests that adolescents and adults perinatally exposed to alcohol, even at low doses, show high prevalence of cognitive impairment and social behavior deficits, which may be in part related to alcohol-induced changes of the gamma-aminobutyric acid (GABA)ergic neurotransmission. The endogenous neurosteroid 3alpha-hydroxy,5alpha-pregnan-20-one (3alpha,5alpha-tetrahydroprogesterone/3alpha,5alpha-THP), a potent positive allosteric modulator of GABA(A) receptor function, is implicated in the physiological tuning of GABA-mediated fast inhibition and in various alcohol's actions in the brain. This study was undertaken to determine whether perinatal exposure to low millimolar blood alcohol concentrations alters cognitive skills (social discrimination and inhibitory avoidance tests), emotional reactivity (elevated plus maze test), and neurosteroid content in brain cortex and hippocampus of adult male offspring. Dams had access to a 3% alcohol solution or to an equicaloric sucrose solution from gestational day 15 to postnatal day 9. Eighty-day old alcohol-exposed male offspring exhibited impaired social recognition memory, but unchanged inhibitory avoidance performance and normal behavior on the elevated-plus maze. The concentrations of 3alpha,5alpha-THP and its precursor progesterone were more than doubled in brain cortex and hippocampus of alcohol-exposed rats, whereas in plasma only progesterone was increased. Thus, exposure to low millimolar blood alcohol concentrations has a long-lasting impact on the developing brain as it causes an impairment of social recognition as well as an increase of brain neurosteroid content in mature animals. The latter may be consequent to altered expression/activity of brain steroidogenic enzymes, as reflected by the enduring increase of the GABA(A) receptor-active neurosteroid 3alpha,5alpha-THP in brain cortex and hippocampus, but not in plasma. It is speculated that, by inducing a greater amplification of GABA(A) receptor function, the elevation of 3alpha,5alpha-THP brain content contributes to the cognitive impairment exhibited by adult alcohol-exposed offspring.
流行病学证据表明，围产期接触酒精的青少年和成年人，即使是低剂量接触，也表现出认知障碍和社会行为缺陷的高患病率，这可能部分与酒精引起的γ-氨基丁酸（GABA）能神经传递变化有关。内源性神经甾体3α-羟基-5α-孕烷-20-酮（3α,5α-四氢孕酮/3α,5α-THP）是GABA(A)受体功能的一种强效正变构调节剂，参与GABA介导的快速抑制的生理调节以及酒精在大脑中的各种作用。本研究旨在确定围产期暴露于低毫摩尔血液酒精浓度是否会改变成年雄性后代的认知技能（社会辨别和抑制性回避测试）、情绪反应性（高架十字迷宫测试）以及大脑皮层和海马体中的神经甾体含量。从妊娠第15天到出生后第9天，母鼠可以饮用3%的酒精溶液或等热量的蔗糖溶液。80日龄的酒精暴露雄性后代表现出社会识别记忆受损，但抑制性回避表现未改变，在高架十字迷宫中的行为正常。酒精暴露大鼠大脑皮层和海马体中3α,5α-THP及其前体孕酮的浓度增加了一倍多，而血浆中只有孕酮增加。因此，暴露于低毫摩尔血液酒精浓度对发育中的大脑有长期影响，因为它会导致社会识别受损以及成熟动物大脑神经甾体含量增加。后者可能是由于大脑甾体生成酶的表达/活性改变所致, 这表现为大脑皮层和海马体中GABA(A)受体活性神经甾体3α,5α-THP持续增加，而血浆中则没有。据推测，通过诱导GABA(A)受体功能的更大增强，3α,5α-THP大脑含量的升高导致成年酒精暴露后代出现认知障碍。
