Cognitive flexibility as a target for relapse prevention

摘要 康复包括用更适应的行为取代饮酒。一旦更适应的行为 养成习惯，康复对先前引起的刺激所产生的复发更具抵抗力 喝酒。然而，在这种转变发生之前，新的自适应行为很容易被取代。这 过渡需要认知上的灵活性，以便处理相关的刺激和意外情况 有了新的行为。不幸的是，大量饮酒会降低认知灵活性，尤其是在 女性。这种认知灵活性的降低似乎是由于α4β2胆碱能活动减少所致 和α7烟碱受体，特别是海马区和前扣带回的受体。 胆碱能神经元起源于内侧隔。恢复胆碱能功能可能会恢复 新学习中的认知灵活性涉及从习惯饮酒到更多饮酒的转变 适应习惯；因此，加快了这一转变。加速这一转变可以最大限度地减少最脆弱的人 恢复期，在新习惯形成之前的早期阶段。然而，越来越多的 胆碱能功能超过最佳水平会损害新的学习。因此，增强胆碱能 也许只有当长期饮酒降低了认知灵活性时，功能才会加速恢复 女性的情况更是如此。我们使用我们开发的大鼠恢复模型来探索这些可能性。喜欢 在现实世界中，在这个模型中，高水平和低水平的饮酒并不是通过改变酒精来控制的 而是通过改变管理替代方案可用性的偶然性，在这方面 箱子里的食物。在只有一种刺激措施的情况下，食品价格昂贵，饮酒占主导地位。当着大家的面 另一方面，食物很容易获得，很少喝水，模拟了康复。在经历了几次 在连续的恢复会议中，大鼠只遇到低成本的食物条件，呈现出 高成本的食品刺激不再控制对乙醇的反应。相反，老鼠坚持做出反应 对于食物，表明这种反应已经成为习惯，并受到高成本食物刺激的控制 被削弱了。我们建议研究慢性间歇性酒精暴露是否会减缓 恢复的发展，以及这种影响是否在女性中更大。此外，我们还比较了两种方法的效果 尼古丁与表巴替丁和PNU-282987相比，后者优先激活α4β2和α7受体， 分别进行了分析。最后，我们检查了尼古丁进入海马体和扣带回的效果。 将这些与丘脑给药后的结果进行比较(预计不会影响认知 灵活性)。该项目探索了预防复发的创新目标：旨在 加快新习惯的养成，比如在行为治疗期间可能会发生的情况。这一战略可能 在康复的早期关键时期减少复发，从而改善治疗结果。

Abstract Recovery involves replacing drinking with more adaptive behavior. Once the more adaptive behavior becomes habitual, recovery is more resistant to relapse produced by stimuli previously occasioning drinking. However, until this transition occurs, the new adaptive behavior is easily displaced. This transition requires cognitive flexibility in order to attend to the stimuli and contingencies associated with the new behavior. Unfortunately, heavy drinking reduces cognitive flexibility, especially in females. This reduced cognitive flexibility appears to result from reduced cholinergic activity at α4β2 and α7 nicotinic receptors, particularly those in the hippocampus and anterior cingulate innervated by cholinergic neurons originating in the medial septum. Restoring cholinergic function may restore cognitive flexibility during the new learning involved in transitioning from habitual drinking to more adaptive habits; and thus, speed this transition. Speeding this transition minimizes the most fragile period of recovery, the early stages before new habits have developed. However, increasing cholinergic function above an optimal level impairs new learning. Thus, enhancing cholinergic function may only speed recovery when chronic drinking has reduced cognitive flexibility, perhaps more so in females. We explore these possibilities using a rat model of recovery we developed. Like in the real world, in this model high and low levels of drinking are controlled not by changing ethanol availability, but rather by changing the contingencies governing the availability of alternatives, in this case food. In the presence of one stimulus, food is costly and drinking predominates. In the presence of another, food is easily available and little drinking occurs, simulating recovery. After several consecutive recovery sessions in which rats only encounter low cost food conditions, presenting the high-cost food stimulus no longer controls responding for ethanol. Instead rats persist at responding for food, indicating this response has become habitual and control by the high-cost food stimulus has weakened. We propose examining whether chronic intermittent ethanol exposure slows the development of recovery, and whether this effect is greater in females. Further, we compare effects of nicotine to those of epibatidine and PNU-282987, which preferentially activate α4β2 and α7 receptors, respectively. Finally, we examine effects of delivering nicotine into the hippocampus and cingulate and compare these to those following administration into the thalamus (not expected to influence cognitive flexibility). This project explores an innovative target for relapse prevention: medications intended to speed new habit formation, such as might occur during behavioral therapy. This strategy may reduce relapse during the early, critical period of recovery, thus improving therapeutic outcomes.