在大鼠中，青春期慢性间歇性乙醇暴露会改变成年期紧张性抑制的乙醇敏感性。
In the rat, chronic intermittent ethanol exposure during adolescence alters the ethanol sensitivity of tonic inhibition in adulthood.
机构信息
Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA.
出版信息
Alcohol Clin Exp Res. 2012 Feb;36(2):279-85. doi: 10.1111/j.1530-0277.2011.01615.x. Epub 2011 Oct 20.
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 ethanol's amnestic effects (White et al., 2000a). We have previously shown that acute ethanol increases tonic inhibitory current mediated by extrasynaptic GABA(A) 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.
背景
青少年饮酒是一个主要的公共卫生问题。青少年倾向于以慢性、间歇性的方式饮酒，即“狂饮”，而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 等人，2000 年；Hunt，1993 年）。青少年人类和大鼠对急性乙醇引起的记忆障碍的敏感性都高于成年人（Acheson 等人，1998 年；Markwiese 等人，1998 年）。此外，在大鼠中，青春期慢性间歇性乙醇（CIE）暴露会导致对乙醇健忘作用的青少年高敏感性长期维持，甚至可能是永久性的（White 等人，2000a）。我们之前已经表明，急性乙醇更有效地增加了青少年大鼠齿状回颗粒细胞（DGC）中由突触外 GABA(A)受体介导的紧张性抑制电流（Fleming 等人，2007）。在这项研究中，我们确定了青春期期间的 CIE 是否会导致这种紧张性电流的长期变化。
方法
将青春期大鼠暴露于 CIE 暴露方案中，并允许其成熟至成年期。在海马脑片的体外全细胞膜片钳测量中，测量了紧张性抑制电流和平均相电流的 tonic 抑制电流。
结果
青春期期间的 CIE 暴露增加了由突触外 GABA(A)受体介导的紧张性抑制电流的乙醇敏感性，并降低了成年 DGC 中由突触 GABA(A)受体介导的相电流的乙醇敏感性。
结论
青春期 CIE 暴露会导致 DGC 中突触外 GABA(A)受体的功能和乙醇敏感性发生长期变化。这些变化似乎“锁定”并维持这些细胞中青少年对乙醇的高敏感性。此外，CIE 后海马结构中紧张性抑制的乙醇增强作用与青少年 CIE 后对乙醇诱导的记忆障碍的敏感性增加一致。这一发现代表了青春期 CIE 期间与记忆相关的细胞长期影响的首次证明，以及这些结果表明的“锁定”青少年对乙醇的敏感性，这可能代表了理解青少年大脑对酒精易感性的概念性进步。
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