Section of Neurobiology and Institute for Neuroscience, Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Texas 78712, USA.
J Neurosci. 2011 Apr 6;31(14):5205-12. doi: 10.1523/JNEUROSCI.5282-10.2011.
Alcohol addiction (alcoholism) is one of the most prevalent substance abuse disorders worldwide. Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug experiences are formed. However, alcohol (ethanol) generally interferes with synaptic plasticity mechanisms in the CNS and thus impairs various types of learning and memory. Therefore, it is unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. Here, using brain slice electrophysiology in mice, we show that repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 d) causes increased susceptibility to the induction of long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated transmission in mesolimbic dopamine neurons, a form of synaptic plasticity that may drive the learning of stimuli associated with rewards, including drugs of abuse. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5-trisphosphate (IP(3)) in producing facilitation of action potential-evoked Ca(2+) signals, which is critical for LTP induction. This increase in IP(3) effect, which lasts for a week but not a month after ethanol withdrawal, occurs through a protein kinase A (PKA)-dependent mechanism. Corticotropin-releasing factor, a stress-related neuropeptide implicated in alcoholism and other addictions, further amplifies the PKA-mediated increase in IP(3) effect in ethanol-treated mice. Finally, we found that ethanol-treated mice display enhanced place conditioning induced by the psychostimulant cocaine. These data suggest that repeated ethanol experience may promote the formation of drug-associated memories by enhancing synaptic plasticity of NMDARs in dopamine neurons.
酒精成瘾（酗酒）是全球最普遍的物质滥用障碍之一。成瘾被认为部分源于适应性学习过程，在此过程中，药物体验的持久记忆形成。然而，酒精（乙醇）通常会干扰中枢神经系统中的突触可塑性机制，从而损害各种类型的学习和记忆。因此，尚不清楚在酗酒发展过程中，与酒精体验相关的强大记忆是如何形成的。在这里，我们使用小鼠脑片电生理学，表明重复的体内乙醇暴露（2 g/kg，腹腔注射，每日三次，持续 7 天）会导致中脑边缘多巴胺神经元中 NMDA 受体（NMDAR）介导的传递长时程增强（LTP）的诱导易感性增加，这是一种可能驱动与奖励相关的刺激学习的突触可塑性形式，包括滥用药物。NMDAR 可塑性的增强是由于肌醇 1,4,5-三磷酸（IP（3））产生易化动作电位诱发的 Ca（2+）信号的效力增加，这对于 LTP 诱导至关重要。这种 IP（3）效应的增加持续一周，但在乙醇戒断后一个月内不会发生，这是通过蛋白激酶 A（PKA）依赖性机制发生的。促肾上腺皮质释放因子，一种与酗酒和其他成瘾有关的应激相关神经肽，进一步放大了 PKA 介导的乙醇处理小鼠中 IP（3）效应的增加。最后，我们发现乙醇处理的小鼠表现出可卡因诱导的位置条件反射增强。这些数据表明，重复的乙醇体验可能通过增强多巴胺神经元中 NMDAR 的突触可塑性来促进与药物相关的记忆的形成。
