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

描述(由申请者提供)：戒除毒瘾和保持戒酒的挑战是双重的。首先，正在康复的吸毒者必须抑制寻求毒品的行为，并实现戒毒。其次，吸毒者必须建立一个新的、非药物强化的、有回报和满足感的行为模式。虽然研究正在确定明确的戒毒训练在减少复吸毒品和复发的脆弱性方面的重要性，但很少有人注意到非药物增强剂在戒毒过程中的作用。本研究使用条件性位置偏好作为情境线索在引出接近行为中的激励价值的度量，系统地考察了新的、非药物强化学习在促进先前药物强化的接近行为消亡中的作用，并评估了非药物促成的消亡对随后的恢复易感性的影响。多巴胺在成瘾中的作用即使不是完全了解，也有很好的文献记录。它被认为在药物强化行为的获得及其表达中都发挥了作用。这个项目研究了一种新的假说，即紧张性多巴胺介导了先前学习的、药物强化的行为的强迫表达，而时相性多巴胺活性调节了先前学习的调节以及新学习的获得，包括非药物强化。因此，一种潜在的治疗策略将是对强直性和相性多巴胺的区别处理。使用转基因小鼠品系，在这些转基因小鼠中，紧张性和相性多巴胺的活性相互独立地改变，研究紧张性和相性多巴胺在消除药物强化行为和获得替代的、非药物行为方面的不同贡献。最后，尼古丁受体已被证明以不同的方式调节紧张性和相性多巴胺的释放，为探索上述假说提供了一种潜在的药理学策略。这个项目将考察目前可用的尼古丁作用药物对药物强化行为的消失和替代的、非药物奖励行为的获得的影响。由于尼古丁受体在调节多巴胺中的作用尚不完全清楚，该项目将使用切片生理学来进一步表征尼古丁对多巴胺的调节，以便为未来的药物开发确定更具体的靶点。 公共卫生相关性：该项目的主要目标是描述非药物奖励在消除已建立的、药物强化的行为中的作用，重点放在可能关键调节这种关系的多巴胺能底物上。提出并开发了一种具体的药理学策略，以促进新的学习和促进寻求药物的灭绝。这项工作将有助于开发更好的成瘾治疗行为方法，进一步阐明在持续康复中至关重要的从药物强化到非药物强化的神经底物，并为特定的药理学靶点提供临床前证据。

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.