Furlong T M, Pan M J, Corbit L H
School of Psychology, University of Sydney, Sydney, NSW, Australia.
Transl Psychiatry. 2015 Sep 1;5(9):e630. doi: 10.1038/tp.2015.130.
Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound-stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg(-1); Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders.
即使经过长时间戒酒，与酒精相关的刺激仍可引发觅酒行为的复发。消除此类刺激可降低其对复发的影响；然而，当在消退学习发生的情境之外进行测试时，消退的表现可能会受到干扰，这种效应称为恢复。行为和药理学方法最近已被证明可增强消退学习；然而，尚不清楚这些治疗后消退表现的改善是否仍依赖于情境。在这里，我们研究了两种方法，即复合刺激消退和用去甲肾上腺素再摄取抑制剂托莫西汀治疗，是否会降低消退对情境变化的易感性。在酒精自我给药后，在一个独特的情境中对反应进行消退。在初始消退后，对与另一种酒精预测性刺激复合呈现的目标刺激进行进一步消退，旨在增加预测误差（实验1），或在全身注射托莫西汀（1.0 mg·kg⁻¹；实验2）后进行。作为复合刺激一部分而消退的刺激引发的反应比单独接受同等消退的刺激少，无论动物是在训练情境还是消退情境中进行测试；然而，在该范式中未观察到可靠的恢复。重要的是，即使存在可靠的恢复效应，托莫西汀相对于对照组仍增强了消退。因此，通过消退多种酒精预测性刺激或在消退训练期间增强去甲肾上腺素神经传递，可以改善觅酒行为的消退。重要的是，即使在消退训练和测试之间情境发生变化，这两种方法都能改善消退，因此可用于提高基于消退的酒精使用障碍治疗的效果。
