Pharmacological Targets Facilitating Non-Drug Reward & Extinction of Drug-Seeking

促进非药物奖励的药理学目标

基本信息

批准号：
7851301
负责人：
JEFF A. BEELER
金额：
$ 34.3万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-19 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7851301
关键词：
Abstinence Affect Animal Model Animals Attention Behavior Behavioral Behavioral Paradigm Corpus striatum structure Cues Development Dopamine Drug Delivery Systems Effectiveness Exhibits Extinction (Psychology)Future Goals Incentives Learning Maintenance Measures Mediating Mus Nicotinic Agonists Nicotinic Receptors Pharmaceutical Preparations Physiological Physiology Play Predisposition Process Recovery Relapse Relative (related person)Research Resistance Rewards Role Slice Testing Therapeutic Training Transgenic Mice Work addiction approach behavior base craving drug development drug reinforcement drug reward drug seeking behavior in vivo interest learning extinction motivated behavior non-drug novel pre-clinical preference presynaptic public health relevance reinforced behavior reinforcer relating to nervous system transmission process

项目摘要

DESCRIPTION (provided by applicant): The challenge in recovering from addiction and maintaining abstinence is two-fold. First, a recovering addict must inhibit drug-seeking behaviors and achieve abstinence. Second, the addict must establish a new, non-drug reinforced behavioral repertoire that is rewarding and satisfying. Although research is establishing the importance of explicit extinction training in reducing vulnerability to reinstatement of drug-seeking and relapse, little attention has been given to the role of non-drug reinforcers in the extinction process. Using conditioned place preference as a measure of the incentive value of contextual cues in eliciting approach behavior, this project systematically examines the role of new, non-drug reinforcement learning in facilitating the extinction of previously, drug- reinforced approach behavior and evaluates the impact of non-drug facilitated extinction on subsequent vulnerability to reinstatement. The role of dopamine in addiction is well documented if not entirely understood. It is believed to play a role both in the acquisition of drug reinforced behavior as well as its expression. This project investigates a novel hypothesis that tonic dopamine mediates the compulsive expression of previously learned, drug-reinforced behaviors while phasic dopamine activity mediates the modulation of previous learning as well as the acquisition of new learning, including non-drug reinforcement. Consequently, a potential therapeutic strategy would be the differential manipulation of tonic and phasic dopamine. Using transgenic mouse lines in which tonic and phasic dopamine activities are altered independent of each other, the differential contribution of tonic and phasic dopamine to the extinction of drug-reinforced behavior and the acquisition of alternative, non-drug behaviors will be investigated. Finally, nicotinic receptors have been shown to differentially modulate tonic and phasic dopamine release, providing a potential pharmacological strategy to pursue the above hypothesis. This project will examine the effects of currently available nicotinic acting drugs on the extinction of drug-reinforced behaviors and the acquisition of alternative, non-drug rewarded behaviors. As the role of nicotinic receptors in modulating dopamine is not fully understood, the project will use slice physiology to further characterize nicotinic modulation of dopamine in order to identify more specific targets for future drug development. PUBLIC HEALTH RELEVANCE: The primary goal of this project is to characterize the role of non-drug reward in the extinction of established, drug-reinforced behavior focusing on dopaminergic substrates that may critically mediate this relationship. A specific pharmacological strategy to enhance new learning and facilitate extinction of drug-seeking is proposed and developed. This work will contribute to the development of better behavioral approaches to addiction treatment, further elucidate the neural substrates underlying the shift from drug- to non-drug reinforcement critical in sustained recovery and provide preclinical evidence for a specific pharmacological target.

描述（申请人提供）：从成瘾和维持禁欲中恢复的挑战是两个方面。首先，康复的成瘾者必须抑制寻求毒品的行为并实现戒酒。其次，瘾君子必须建立一个新的非药品增强行为曲目，这是有益和令人满意的。尽管研究确立了明确灭绝训练在减少恢复毒品和复发的脆弱性方面的重要性，但很少关注非毒品增强剂在灭绝过程中的作用。该项目使用条件地位偏好作为衡量上下文提示在引发方法行为中的激励价值的衡量值，该项目系统地研究了新的非药物增强学习在促进以前的灭绝，药物增强方法行为的灭绝中的作用，并评估非戒毒的影响，对随后的脆弱性的灭绝影响。多巴胺在成瘾中的作用也有充分的文献证明，即使不是完全了解。人们认为它在获取药物增强行为及其表达中都起着作用。该项目研究了一个新的假设，即补胺多巴胺介导了先前学到的，药物增强的行为的强迫性表达，而阶段性多巴胺活性则介导了先前学习的调节以及新学习的获取，包括非毒品强化。因此，潜在的治疗策略将是补品和阶段多巴胺的差异操纵。使用滋补和阶段性多巴胺活性相互独立改变的转基因小鼠系，将研究滋补和阶段多巴胺对药物增强行为灭绝的差异贡献，并研究替代性，非毒品行为。最后，烟碱受体已显示出差异性调节补品和阶段性多巴胺的释放，从而提供了一种潜在的药理策略来追求上述假设。该项目将研究当前可用的烟碱作用药物对药物增强行为的灭绝以及获得替代性，非毒品奖励行为的影响。由于烟碱受体在调节多巴胺中的作用尚不完全了解，因此该项目将使用切片生理学来进一步表征多巴胺的烟碱调节，以确定未来药物开发的更具体的靶标。公共卫生相关性：该项目的主要目的是表征非药物奖励在灭绝的既定，毒品强化行为的灭绝中的作用，该行为重点是多巴胺能底物，这些底物可能会严重调解这种关系。提出并开发了一种特定的药理策略，以增强新的学习和促进灭绝药物的灭绝。这项工作将有助于发展成瘾治疗的更好行为方法，进一步阐明从药物转移到非药物恢复至关重要的转移至关重要的持续恢复至关重要的神经底物，并为特定的药理目标提供了临床前证据。