INSERM, UMR 1247 GRAP, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Univ Picardie Jules Verne, Centre Universitaire de Recherche en Santé (CURS), Amiens, France.
Addict Biol. 2021 Jul;26(4):e13002. doi: 10.1111/adb.13002. Epub 2021 Jan 28.
Binge drinking during adolescence induces memory impairments, and evidences suggest that females are more vulnerable than males. However, the reason for such a difference is unclear, whereas preclinical studies addressing this question are lacking. Here we tested the hypothesis that endogenous estrogen level (E2) may explain sex differences in the effects of ethanol on hippocampus plasticity, the cellular mechanism of memory. Long-term depression (LTD) in hippocampus slice of pubertal female rats was recorded 24 h after two ethanol binges (3 g/kg, i.p., 9 h apart). Neither the estrous cycle nor ethanol altered LTD. However, if ethanol was administered during proestrus (i.e., at endogenous E2 peak), LTD was abolished 24 h later, whereas NMDA-fEPSPs response to a GluN2B antagonist increased. The abolition of LTD was not observed in adult female rats. Exogenous E2 combined with ethanol replicated LTD abolition in pubertal, prepubertal female, and in pubertal male rats without changes in ethanol metabolism. In male rats, a higher dose of ethanol was required to abolish LTD at 24-h delay. In pubertal female rats, tamoxifen, an antagonist of estrogen receptors, blocked the impairing effects of endogenous and exogenous E2 on LTD, suggesting estrogen interacts with ethanol through changes in gene expression. In addition, tamoxifen prevented LTD abolition at 24 h but not at 48-h delay. In conclusion, estrogen may explain the increased vulnerability to ethanol-induced plasticity impairment seen in females compared with males. This increased vulnerability of female rats is likely due to changes in the GluN2B subunit that represent a common target between ethanol and estrogen.
青少年时期的狂饮会导致记忆力减退，有证据表明女性比男性更容易受到影响。然而，造成这种差异的原因尚不清楚，而针对这一问题的临床前研究也很缺乏。在这里，我们检验了这样一个假设，即内源性雌激素水平（E2）可能解释了乙醇对海马体可塑性（记忆的细胞机制）影响的性别差异。在青春期雌性大鼠的海马体切片中记录了两次乙醇狂饮（3g/kg，腹腔注射，间隔 9 小时）24 小时后的长时程压抑（LTD）。发情周期和乙醇都没有改变 LTD。然而，如果在发情前期（即内源性 E2 高峰时）给予乙醇，24 小时后 LTD 就会被消除，而 NMDA-fEPSPs 对 GluN2B 拮抗剂的反应增加。在成年雌性大鼠中没有观察到 LTD 的消除。外源性 E2 结合乙醇可在青春期、青春期前雌性和青春期雄性大鼠中复制 LTD 的消除，而不改变乙醇的代谢。在雄性大鼠中，需要更高剂量的乙醇才能在 24 小时延迟后消除 LTD。在青春期雌性大鼠中，他莫昔芬（一种雌激素受体拮抗剂）阻断了内源性和外源性 E2 对 LTD 的损害作用，这表明雌激素通过改变基因表达与乙醇相互作用。此外，他莫昔芬可预防 LTD 在 24 小时但不能在 48 小时延迟时消除。总之，雌激素可能解释了女性比男性更容易受到乙醇引起的可塑性损伤的原因。与雄性大鼠相比，雌性大鼠的这种易感性增加可能是由于 GluN2B 亚基的变化所致，该亚基是乙醇和雌激素之间的共同靶点。
