Therapeutic Approaches for Extinction of Conditioned Drug Reward

描述（由申请人提供）： 处方阿片剂的非医疗使用和滥用正在上升，其流行率超过海洛因或可卡因滥用。在军事和退伍军人管理局的设置，士兵和退伍军人面临急性或慢性疼痛，这是管理的阿片类麻醉剂和滥用这些代理人被广泛报道。行为疗法和阿片类药物替代治疗阿片类药物成瘾是时间密集型的方法，不完全有效，往往无法获得。在吸毒期间，个人暴露于环境线索或滥用药物的背景下。强烈的药物线索或情境偏好的发展加速了从间歇性药物使用到药物成瘾的转变。未来暴露于这些相同的线索，会通过联想学习过程诱发条件性寻求行为和复发。本研究探讨了增强这些条件性药物反应消退的神经生物学机制和治疗方法。我们提出的临床前研究探讨了条件性阿片奖励（COR）及其消退的机制，并在C57 BL/6小鼠中测试了新的药理学和行为消退学习方法。 先前的研究表明，重复的阿片类药物给药改变了大脑皮层和边缘系统区域的突触可塑性，而这些区域是成瘾相关行为的基础。我们假设，反复条件反射与吗啡产生COR是由可塑性介导的动机和认知神经回路。我们建立了一个阿片类药物诱导的条件性位置偏爱（CPP）模型，在该模型中，线索和情境偏好可以被测量，然后在无药物环境中通过重复的情境暴露而被消除。我们假设COR的消失是一个新的学习过程，导致学习反应的频率或强度降低。据推测，COR涉及中皮质边缘多巴胺神经元（如前额叶皮质（PFC）和基底外侧杏仁核（BLA））中脑源性神经营养因子（BDNF）的增加。阿片成瘾的可塑性与BDNF增加树突棘蛋白质合成、改变连接性和调节COR消退中的长期记忆的能力有关。我们推测，脑源性神经营养因子在PFC区域的输液增强了CPP的灭绝和阻断引发诱导的COR的恢复。我们推测，其他增强BDNF可塑性的药理学方法也增加了消退的速度和/或程度，并减少引发诱导的CPP恢复。我们的研究使用组蛋白去乙酰化酶抑制剂（HDACi）治疗增强BDNF可塑性，熄灭COR，减少引发诱导的COR重新获得。 我们的目的是研究BDNF和神经营养酪氨酸激酶受体（TrkB）受体机制在中脑边缘多巴胺和前额叶皮层神经元在COR及其灭绝。我们建议检查前额叶皮层BDNF/TrkB信号传导对CPP消退及其引发诱导的COR恢复的治疗效果。最后，我们建议使用临床上可用的HDACi、丁酸钠和丙戊酸盐来检查BDNF的表观遗传调节对COR的消退和引发诱导的恢复的治疗效果。这项转化研究可以直接推进新的药理学和行为学方法，以消除成瘾中的药物线索和背景反应，并可以为阿片类药物滥用退伍军人的临床试验设计提供信息。 公共卫生相关性： 物质使用是一个巨大的社会问题，影响着美国2100万人。最近药物滥用发生率增加最多的是阿片类止痛剂的非医疗使用（220万人）。迫切需要为数百万滥用阿片类麻醉品的美国人提供新的有效治疗方法。开发新的非成瘾药物治疗方案可以增加线索暴露，动机和认知心理治疗方法。与退伍军人健康的相关性-滥用阿片类止痛药是退伍军人事务部的一个大问题。近一半的OEF/OIF退伍军人在服役后经历持续或新的疼痛。有疼痛的退伍军人被规定使用阿片类止痛药，并有滥用的风险。该提案研究了新的治疗方法，使用药理学和行为治疗来消除动物模型中的线索反应。这些方法可以为阿片类药物滥用退伍军人的未来临床试验提供信息。

DESCRIPTION (provided by applicant): Non-medical use and abuse of prescription opiates is rising so that its prevalence is greater than that of heroin or cocaine abuse. In military and VA settings, soldiers and Veterans face acute or chronic pain that is managed by opiate narcotics and misuse of these agents is widely reported. Behavioral therapies and opiate substitution treatment for opiate addiction are time-intensive approaches that are incompletely effective and often inaccessible. During drug-taking, individuals are exposed to environmental cues or contexts where drugs of abuse are administered. The development of strong drug cue or contextual preferences accelerates the transition from intermittent drug use to drug addiction. Future exposure to these same cues elicits conditioned seeking behaviors and relapse via associative learning processes. This proposal examines the neurobiological mechanisms and treatment approaches to enhance the extinction of these conditioned drug responses. Our proposed preclinical research examines mechanisms of conditioned opiate reward (COR) and its extinction and tests novel pharmacological and behavioral extinction learning approaches in C57BL/6 mice. Previous research has shown that repeated opiate administration alters synaptic plasticity in cortical and limbic regions which underlie addiction-related behaviors. We hypothesize that repeated conditioning with morphine produces COR that is mediated by plasticity in motivational and cognitive neural circuits. We have established a model of opiate-induced conditioned place preference (CPP) in which cue and contextual preferences can be measured and then extinguished by repeated contextual exposure in a drug-free environment. We hypothesize that the extinction of COR is a new learning process that results in a decrease in the frequency or intensity of learned responses. COR is hypothesized to involve increases in brain derived neurotrophic factor (BDNF) in mesocorticolimbic dopamine neurons such as prefrontal cortex (PFC) and basolateral amygdala (BLA). Plasticity in opiate addiction is proposed to relate to BDNF's ability to increase protein synthesis in dendritic spines, alter connectivity and regulate long-term memory in COR extinction. We hypothesize that infusion of BDNF in PFC regions enhances the extinction of CPP and blocks priming-induced reinstatement of COR. We hypothesize that other pharmacological approaches which enhance BDNF plasticity also increase the rate and/or extent of extinction and reduce priming-induced reinstatement of CPP. Our studies use histone deacetylase inhibitor (HDACi) treatment for enhancing BDNF plasticity, extinguishing COR, and reducing priming-induced reacquisition of COR. Our aims will examine the BDNF and neurotrophic tyrosine kinase receptor (TrkB) receptor mechanisms in mesolimbic dopamine and prefrontal cortical neurons during COR and its extinction. We propose to examine the treatment effects of prefrontal cortical BDNF/TrkB signaling on the extinction of CPP and its priming- induced reinstatement of COR. Finally, we propose to examine the treatment effects of epigenetic regulation of BDNF using clinically available HDACi's, sodium butyrate and valproate, on the extinction and priming-induced reinstatement of COR. This translational research can directly advance new pharmacological and behavioral approaches to extinguish drug cue and contextual reactivity in addiction and can inform the design of clinical trials for opiate abusing Veterans. PUBLIC HEALTH RELEVANCE: Significance- Substance use is an enormous societal problem affecting 21 million persons in the US. The largest increase in recent drug abuse incidence is in the nonmedical use of opiate pain relievers (2.2 million persons). Access to new and effective therapeutic approaches for the millions of Americans who misuse opiate narcotics is desperately needed. The development of new non-addictive pharmacotherapeutic treatment regiments can augment cue exposure, motivational and cognitive psychotherapeutic approaches. Relevance to Veterans Health- Misuse of opiate pain relievers is a large concern in the VA. Nearly half of OEF/OIF veterans experience ongoing or new pain after service. Veterans with pain are prescribed opiate pain relievers and are at risk for their misuse. This proposal examines new treatment approaches using pharmacological and behavioral treatments to extinguish cue reactivity in an animal model. Such approaches can inform future clinical trials for opiate abusing veterans.