Breese George R, Overstreet David H, Knapp Darin J
Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina School of Medicine, 3007 Thurston-Bowles Building CB-7178, Chapel Hill, NC 27599-7178, USA.
Psychopharmacology (Berl). 2005 Apr;178(4):367-80. doi: 10.1007/s00213-004-2016-2. Epub 2004 Oct 23.
The rationale for proposing the "kindling"/stress hypothesis is to provide a conceptual basis for the insidious development and maintenance of alcohol abuse.
An objective of the hypothesis is to emphasize how continued alcohol abuse is linked to progressive neural adaptation. Work has shown that repeated withdrawals from chronic low levels of alcohol sensitize ("kindle") anxiety-like behavior ("anxiety") in rats, a finding consistent with multiple withdrawal kindling of seizure activity. Additionally, stress substitutes for initial cycles of the multiple withdrawal protocol to sensitize withdrawal-induced anxiety, which is indicative that stress is capable of facilitating neuroadaptive processes related to withdrawal. The persistence of adaptation caused by stress and multiple withdrawals is revealed by the appearance of withdrawal-induced anxiety following a future re-exposure to a single 5-day period of alcohol. This persisting adaptation also permits stress to induce anxiety during a period of abstinence--a response not observed in animals without previous exposure to alcohol. Furthermore, stress interacts with repeated withdrawals to enhance voluntary alcohol drinking. Results of other preclinical and clinical studies reported in the literature are integrated with these investigations in support of the proposed hypothesis.
The "kindling"/stress hypothesis is based on the premise that repeated withdrawals from cycles of chronic alcohol exposure contribute to a progressive development of persisting adaptive change that sensitizes withdrawal-induced anxiety and allows stress to evoke symptoms associated with negative affect during abstinence. Thus, these consequences of repeated withdrawals account for the evolution of major characteristics of alcoholism, which include worsened acute withdrawal symptoms and increased stress-induced negative affect during abstinence, both of which enhance the likelihood of relapse--and with relapse an inability to limit an abusive pattern of alcohol intake. The "kindling"/stress hypothesis provides a clear strategy for future studies to explore the advancing neural adaptation proposed to contribute to the pathogenesis of alcoholism.
提出“点燃”/应激假说的目的是为酒精滥用的隐匿发展和维持提供一个概念基础。
该假说的一个目的是强调持续的酒精滥用如何与渐进性神经适应相关联。研究表明，从慢性低剂量酒精中反复戒断会使大鼠的焦虑样行为（“焦虑”）敏感化（“点燃”），这一发现与癫痫活动的多次戒断点燃相一致。此外，应激可替代多次戒断方案的初始周期，使戒断诱导的焦虑敏感化，这表明应激能够促进与戒断相关的神经适应过程。未来再次接触为期5天的单一酒精周期后出现的戒断诱导焦虑，揭示了应激和多次戒断所导致的适应的持续性。这种持续的适应还使得应激在禁欲期间诱发焦虑——这一反应在未预先接触酒精的动物中未观察到。此外，应激与反复戒断相互作用，增强自愿饮酒行为。文献中报道的其他临床前和临床研究结果与这些研究相结合，以支持所提出的假说。
“点燃”/应激假说基于这样一个前提，即从慢性酒精暴露周期中反复戒断会导致持续性适应性变化的渐进发展，这种变化会使戒断诱导的焦虑敏感化，并使应激在禁欲期间引发与负面影响相关的症状。因此，反复戒断的这些后果解释了酒精中毒主要特征的演变，包括急性戒断症状加重以及禁欲期间应激诱导的负面影响增加，这两者都增加了复发的可能性——而且随着复发，无法限制酒精摄入的滥用模式。“点燃”/应激假说为未来研究探索所提出的导致酒精中毒发病机制的渐进性神经适应提供了一个明确的策略。
