Therapeutic Approaches for Extinction of Conditioned Drug Reward

描述(由申请人提供)： 处方鸦片类药物的非医疗用途和滥用正在增加，其流行率超过海洛因或可卡因滥用。在军事和退伍军人环境中，士兵和退伍军人面临由鸦片类麻醉剂控制的急性或慢性疼痛，滥用这些药物的情况被广泛报道。行为疗法和阿片类药物替代疗法是治疗阿片成瘾的耗时方法，不完全有效，而且往往无法获得。在吸毒期间，个人暴露在使用滥用药物的环境线索或环境中。强烈的药物线索或背景偏好的发展加速了从间歇性药物使用到药物成瘾的转变。未来暴露在这些相同的线索下，会引发条件性寻求行为，并通过联想学习过程复发。这项建议审查了神经生物学机制和治疗方法，以加强这些条件药物反应的消退。我们提出的临床前研究检验了条件性阿片奖励(COR)及其消退的机制，并在C57BL/6小鼠身上测试了新的药理和行为消退学习方法。先前的研究表明，重复服用阿片类药物会改变大脑皮质和边缘区域的突触可塑性，这是成瘾相关行为的基础。我们假设，反复使用吗啡产生的COR是由动机和认知神经回路中的可塑性调节的。我们已经建立了一个阿片剂诱导的条件性位置偏好(CPP)模型，在该模型中，线索和语境偏好可以被测量，然后通过在无药物环境中的重复语境暴露而消失。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。COR被认为涉及大脑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。阿片成瘾的可塑性被认为与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，在PFC区注入BDNF可增强CPP的消退，并阻断预激诱导的COR的恢复。我们假设，其他增强BDNF可塑性的药理学方法也可以增加CPP的消退速度和/或程度，并减少启动诱导的CPP的恢复。我们的研究使用组蛋白脱乙酰酶抑制剂(HDACi)治疗，以增强BDNF的可塑性，消除COR，并减少预充诱导的COR的再获得。我们的目标将研究脑源性神经营养因子和神经营养酪氨酸激酶受体(TrkB)受体在COR及其消退过程中在中脑边缘多巴胺和前额叶皮质神经元中的作用机制。我们建议研究前额叶皮质BDNF/TrkB信号在CPP消退及其引发的COR恢复中的治疗作用。最后，我们建议用临床上可用的HDACi、丁酸钠和丙戊酸盐来检验BDNF的表观遗传调节对COR消退和启动诱导的恢复的治疗效果。这项转化研究可以直接推动新的药理学和行为方法来消除成瘾中的药物线索和上下文反应，并可以为阿片滥用退伍军人的临床试验设计提供信息。 公共卫生相关性： 意义--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药的非医疗用途(220万人)。数百万滥用鸦片类麻醉剂的美国人迫切需要获得新的有效治疗方法。开发新的非成瘾性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-阿片类止痛药的滥用是退伍军人管理局的一大担忧。近一半的OEF/OIF退伍军人在服役后经历持续或新的疼痛。有疼痛的退伍军人会被开出阿片类止痛药的处方，并面临滥用的风险。这项建议研究了新的治疗方法，使用药物和行为治疗来消除动物模型中的线索反应性。这种方法可以为未来阿片滥用退伍军人的临床试验提供信息。

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.