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

描述（由申请人提供）：从成瘾中恢复并保持戒断的挑战是双重的。首先，一个正在康复的瘾君子必须抑制寻求毒品的行为并达到戒断。第二，上瘾者必须建立一种新的、非药物强化的、有益的、令人满意的行为准则。虽然研究正在确立明确的消退训练在减少重新寻求药物和复发的脆弱性方面的重要性，但很少注意到非药物强化物在消退过程中的作用。本项目使用条件位置偏好作为情境线索在诱导接近行为中的激励价值的衡量标准，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失中的作用，并评估了非药物促进的消失对随后恢复脆弱性的影响。多巴胺在成瘾中的作用虽未被完全理解，但已被充分证明。它被认为在药物强化行为的习得及其表达中都起作用。本项目研究了一种新的假设，即强直性多巴胺介导先前学习和药物强化行为的强迫性表达，而相性多巴胺活动介导先前学习和新学习的调节，包括非药物强化。因此，一种潜在的治疗策略可能是对强直性和阶段性多巴胺的不同操作。研究人员将利用相互独立改变强直多巴胺和相多巴胺活性的转基因小鼠品系，研究强直多巴胺和相多巴胺对药物增强行为的消失和替代非药物行为的获得的差异贡献。最后，烟碱受体已被证明对强力性和阶段性多巴胺释放有差异调节，为上述假设提供了一种潜在的药理学策略。该项目将检查目前可用的尼古丁作用药物对药物强化行为的消失和获得替代，非药物奖励行为的影响。由于尼古丁受体在多巴胺调节中的作用尚不完全清楚，该项目将利用切片生理学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。

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.