Cognitive flexibility as a target for relapse prevention

认知灵活性作为预防复发的目标

• 批准号: 10399580
• 负责人: BRETT C GINSBURG
• 金额: $ 34.12万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399580
• 关键词: Adaptive Behaviors; Agonist; Alcohol abuse; Anterior; Behavior; Behavior Therapy; Behavioral; Brain; Brain region; Chronic; Cognitive; Cues; Development; Ethanol; Exposure to; Family; Female; Food; Goals; Habits; Heavy Drinking; Hippocampus (Brain); Impairment; Individual; Injections; Lead; Learning; Maintenance; Medial; Memory; Modeling; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Outcome; Pharmaceutical Preparations; Pharmacology; Psychological reinforcement; Rattus; Recording of previous events; Recovery; Relapse; Resistance; Speed; Stimulus; Thalamic structure; Time; Training; alcohol availability; alcohol effect; alcohol exposure; alcohol seeking behavior; cholinergic; cholinergic neuron; cingulate cortex; cognitive enhancement; cost; critical period; disorder later incidence prevention; drinking; epibatidine; flexibility; improved; innovation; male; neurotransmission; prevent; problem drinker; receptor; response; sex; side effect; therapy outcome

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.

摘要 恢复包括用更适应的行为取代饮酒。一旦更适应的行为 一旦成为习惯，恢复就更能抵抗先前刺激所产生的复发。 喝酒然而，在这种转变发生之前，新的适应行为很容易被取代。这 过渡需要认知的灵活性，以便注意到相关的刺激和突发事件 新的行为。不幸的是，大量饮酒会降低认知灵活性，特别是在 女性这种认知灵活性的降低似乎是由于α4β2胆碱能活性的降低。 和α7烟碱受体，特别是海马和前扣带回中的受体， 起源于内侧隔的胆碱能神经元。恢复胆碱能功能可以恢复 在新的学习过程中，认知灵活性涉及从习惯性饮酒到更多饮酒的转变。 适应性习惯，从而加速这种转变。加快这一转变， 恢复期，新习惯形成之前的早期阶段。然而，日益 高于最佳水平的胆碱能功能损害新的学习。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， 女性更是如此。我们使用我们开发的大鼠恢复模型来探索这些可能性。像 在真实的世界中，在这个模型中，饮酒量的高低不是通过改变乙醇来控制的 可用性，而是通过改变控制替代品可用性的突发事件， 个案食品在一种刺激存在的情况下，食物是昂贵的，饮酒占主导地位。存在下 在另一种情况下，食物很容易获得，很少饮酒，模拟恢复。经过几 连续的恢复期，其中大鼠只遇到低成本的食物条件， 高成本的食品刺激不再控制对乙醇的反应。相反，老鼠坚持回应 对于食物，这表明这种反应已经成为习惯，高成本食物刺激的控制已经成为习惯。 变弱了我们建议检查慢性间歇性乙醇暴露是否会减缓 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 尼古丁与地棘蛙素和PNU-282987相比，前者优先激活α4β2和α7受体， 分别最后，我们研究了将尼古丁输送到海马和扣带回的影响， 将这些与给药至丘脑后的那些进行比较（预期不会影响认知能力 灵活性）。该项目探索了预防复发的创新目标： 加速新习惯的形成，例如在行为治疗期间可能发生的。这种策略可能 在早期关键的康复期减少复发，从而改善治疗效果。