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

描述（由申请人提供）：从成瘾中恢复和保持戒断的挑战是双重的。首先，一个正在康复的吸毒者必须抑制寻求毒品的行为，实现禁欲。第二，成瘾者必须建立一个新的，非药物强化的行为曲目，是奖励和满意。虽然研究正在确定明确的灭绝训练在减少吸毒和复吸的脆弱性方面的重要性，但很少有人关注非毒品成瘾者在灭绝过程中的作用。使用条件性位置偏好作为情境线索在诱发接近行为中的激励价值的度量，该项目系统地检查了新的非药物强化学习在促进先前药物强化的接近行为的消退中的作用，并评估了非药物促进的消退对随后恢复的脆弱性的影响。多巴胺在成瘾中的作用是有据可查的，如果不是完全理解。它被认为在药物强化行为的获得及其表达中发挥作用。该项目研究了一个新的假设，即紧张性多巴胺介导先前学习的强迫性表达，药物强化行为，而阶段性多巴胺活性介导先前学习的调制以及新学习的获得，包括非药物强化。因此，一个潜在的治疗策略将是紧张性和相位多巴胺的差异操纵。使用转基因小鼠品系，其中紧张性和相位多巴胺活动的改变彼此独立，紧张性和相位多巴胺的药物强化行为的灭绝和收购的替代，非药物行为的差异贡献将进行调查。最后，烟碱受体已被证明差异调节紧张性和阶段性多巴胺释放，提供了一个潜在的药理学策略，以追求上述假设。这个项目将研究目前可用的尼古丁作用药物对药物强化行为的消除和替代性非药物奖励行为的获得的影响。由于烟碱受体在调节多巴胺中的作用尚未完全了解，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已建立的药物强化行为灭绝中的作用，重点是可能关键介导这种关系的多巴胺能底物。一个具体的药理学策略，以提高新的学习和促进灭绝的药物寻求的建议和发展。这项工作将有助于开发更好的成瘾治疗行为方法，进一步阐明从药物到非药物强化转变的神经基质，这对持续康复至关重要，并为特定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.