In the Rat, Chronic Intermittent Ethanol Exposure During Adolescence Alters the Ethanol Sensitivity of Tonic Inhibition in Adulthood
In the Rat, Chronic Intermittent Ethanol Exposure During Adolescence Alters the Ethanol Sensitivity of Tonic Inhibition in Adulthood
复制标题
DOI：
10.1111/j.1530-0277.2011.01615.x
复制
发表时间：
2012-02-01
影响因子：
3.2
通讯作者：
Swartzwelder, H. Scott
中科院分区：
文献类型：
--
作者：
Fleming, Rebekah L.;Acheson, Shawn K.;Swartzwelder, H. Scott
背景：青少年饮酒是一个主要的公共卫生问题。青少年倾向于慢性、间歇性饮酒，即暴饮暴食，这种乙醇暴露模式与神经毒性风险增加和酒精使用障碍的发展有关（Crews 等，2000；Hunt，1993）。青少年和大鼠都比成年人对急性乙醇引起的记忆障碍更敏感（Acheson 等，1998；Markwiese 等，1998）。此外，在大鼠中，青春期期间慢性间歇性乙醇（CIE）暴露会导致青少年对乙醇记忆删除效应的高度敏感性长期持续，甚至可能永久维持（White et al., 2000a）。我们之前已经表明，与成年大鼠相比，急性乙醇可以更有效地增加青少年齿状颗粒细胞（DGC）中突触外 GABAA 受体介导的强直抑制电流（Fleming 等，2007）。在这项研究中，我们确定青春期期间的 CIE 是否会在这种强直电流中产生持久的变化。方法：对青春期大鼠进行 CIE 暴露方案，并使其成熟至完全成年。在海马脑切片中进行体外全细胞电压钳测量强直抑制电流和平均相电流。结果：青春期 CIE 暴露增加了突触外 GABA(A) 受体介导的强直抑制电流的乙醇敏感性，并降低了成年 DGC 中突触外 GABA(A) 受体介导的相位电流的乙醇敏感性。结论：青春期 CIE 暴露会导致功能的持久变化DGC 中突触外 GABA(A) 受体的乙醇敏感性。这些变化似乎“锁定”并维持了这些细胞中青少年对乙醇的高度敏感性。此外，CIE后海马结构中的强直抑制的乙醇增强与青少年CIE后对乙醇引起的记忆损伤的更大敏感性一致。这一发现首次证明了CIE在青春期期间与记忆相关的长期细胞效应，并且这些结果表明青少年乙醇敏感性的“锁定”可能代表在理解青少年大脑对酒精的脆弱性方面向前迈出了概念性的一步。
Background: Alcohol drinking by adolescents is a major public health concern. Adolescents tend to drink in a chronic, intermittent, that is, binge, pattern, and such patterns of ethanol exposure are associated with increased risk of neurotoxicity and the development of alcohol use disorders (Crews et al., 2000; Hunt, 1993). Both adolescent humans and rats are more sensitive to acute ethanol-induced memory impairment than adults (Acheson et al., 1998; Markwiese et al., 1998). Furthermore, in rats, chronic intermittent ethanol (CIE) exposure during adolescence produces a long-lasting, perhaps permanent, maintenance of the adolescent high sensitivity to ethanols amnestic effects (White et al., 2000a). We have previously shown that acute ethanol increases tonic inhibitory current mediated by extrasynaptic GABAA receptors more efficaciously in dentate granule cells (DGCs) from adolescent than adult rats (Fleming et al., 2007). In this study, we determined if CIE during adolescence produced long-lasting changes in this tonic current.Methods: Adolescent rats were subjected to a CIE exposure regimen and allowed to mature to full adulthood. Whole-cell voltage-clamp measurements of tonic inhibitory current and mean phasic current were made in vitro in hippocampal brain slices.Results: CIE exposure during adolescence increased the ethanol sensitivity of tonic inhibitory current mediated by extrasynaptic GABA(A) receptors and decreased the ethanol sensitivity of phasic, synaptic GABA(A) receptor-mediated current in adult DGCs.Conclusions: CIE exposure during adolescence produces long-lasting changes in the function and ethanol sensitivity of extrasynaptic GABA(A) receptors in DGCs. These changes appear to "lock-in'' and maintain the high adolescent sensitivity to ethanol in these cells. Furthermore, greater ethanol enhancement of tonic inhibition in the hippocampal formation after CIE is consistent with the greater sensitivity to ethanol-induced memory impairment after adolescent CIE. This finding represents the first demonstration of a long-term, memory-related cellular effect of CIE during adolescence, and the "lock-in'' of adolescent ethanol sensitivity that these results suggest could represent a conceptual step forward in understanding the vulnerability of the adolescent brain to alcohol.