Li Qiang, Wilson Wilkie A, Swartzwelder H S
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27705, USA.
Alcohol Clin Exp Res. 2006 Jan;30(1):119-26. doi: 10.1111/j.1530-0277.2006.00006.x.
Ethanol (EtOH) consumption by juveniles and adolescents is an important public health problem. Recent studies have indicated that adolescent animals are less sedated by EtOH than adult animals and experience less motor impairment. Thus, human adolescents may be able to consume more EtOH prior to sedation, putting them at greater risk for EtOH addiction and other negative consequences of EtOH use. However, the mechanisms underlying this developmental difference are unknown. One contributing factor may be gamma-aminobutyric acid-A (GABA(A)) receptor-mediated inhibition, which is known to produce sedation. We have shown that evoked, GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) are less powerfully enhanced by EtOH in neurons from juvenile or adolescent animals than in those from adult animals; however, the mechanisms of this developmental difference in sensitivity are unknown.
Using whole-cell recording, we tested the response of spontaneous and miniature GABA(A) receptor-mediated IPSCs (sIPSCs and mIPSCs) to EtOH in rat hippocampal slices from animals representing two distinct developmental stages: adolescent and adult.
We found significantly greater EtOH-induced enhancement of the frequency of sIPSCs in cells from adult animals compared to those from adolescent animals. Although EtOH also increased the frequency of mIPSCs, this effect was not age dependent. EtOH did not significantly affect the kinetics of mIPSCs.
We conclude that the sensitivity of GABA(A) receptor-mediated inhibitory processes to EtOH increases with development from the adolescent period to adulthood, and that this is likely mediated by developmental changes in the effect of EtOH on interneuron excitation.
青少年饮酒是一个重要的公共卫生问题。最近的研究表明，与成年动物相比，青少年动物对乙醇（EtOH）的镇静作用更不敏感，运动功能受损也较轻。因此，人类青少年在镇静前可能能够摄入更多的EtOH，这使他们更容易成瘾以及出现其他乙醇使用带来的负面后果。然而，这种发育差异背后的机制尚不清楚。一个可能的因素是γ-氨基丁酸-A（GABA(A)）受体介导的抑制作用，已知其会产生镇静作用。我们已经表明，在幼年或青少年动物的神经元中，诱发的GABA(A)受体介导的抑制性突触后电流（IPSCs）受EtOH增强的程度不如成年动物神经元中的明显；然而，这种敏感性发育差异的机制尚不清楚。
我们使用全细胞记录技术，测试了代表两个不同发育阶段（青少年和成年）的大鼠海马切片中，自发性和微小GABA(A)受体介导的IPSCs（sIPSCs和mIPSCs）对EtOH的反应。
我们发现，与青少年动物的细胞相比，EtOH诱导成年动物细胞中sIPSCs频率增加的幅度明显更大。虽然EtOH也增加了mIPSCs的频率，但这种效应不依赖于年龄。EtOH对mIPSCs的动力学没有显著影响。
我们得出结论，从青少年期到成年期，GABA(A)受体介导的抑制过程对EtOH的敏感性随着发育而增加，这可能是由EtOH对中间神经元兴奋作用的发育变化介导的。
