Therapeutic Approaches for Extinction of Conditioned Drug Reward

条件药物奖励消除的治疗方法

• 批准号: 8597381
• 负责人: Gary B. Kaplan
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597381
• 关键词: Acute Pain; Affect; Alcohol or Other Drugs use; American; Amygdaloid structure; Analgesics; Animal Model; Behavior; Behavior Therapy; Behavioral; Brain-Derived Neurotrophic Factor; C57BL/6 Mouse; Clinical Trials; Clinical Trials Design; Cocaine Abuse; Cognitive; Cues; Dendritic Spines; Development; Dopamine; Drug Addiction; Drug abuse; Drug usage; Environment; Epigenetic Process; Exposure to; Extinction (Psychology); Face; Frequencies; Future; Health; Heroin Abuse; Histone Deacetylase Inhibitor; Incidence; Individual; Infusion procedures; Learning; Measures; Mediating; Medical; Military Personnel; Modeling; Morphine; Narcotics; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Opiate Addiction; Opiates; Pain; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Prefrontal Cortex; Prevalence; Process; Protein Biosynthesis; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Relapse; Reporting; Research; Rewards; Risk; Services; Signal Transduction; Sodium Butyrate; Soldier; Synaptic plasticity; Testing; Therapeutic; Time; Translational Research; Veterans; addiction; chronic pain; classical conditioning; conditioning; cue reactivity; dopaminergic neuron; drug of abuse; drug reward; experience; long term memory; neural circuit; neurobiological mechanism; nonmedical use; novel; opioid abuse; pre-clinical research; preference; prescription opiate; public health relevance; response; treatment effect; valproate

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.

描述（由申请人提供）： 非医学使用和滥用处方鸦片的使用正在上升，因此其患病率大于海洛因或可卡因滥用。在军事和VA环境中，士兵和退伍军人面临急性或慢性疼痛，这些疼痛是通过鸦片麻醉和滥用这些特工管理的。行为疗法和阿片类替代治疗阿片成瘾是时间密集型方法，这些方法是不完全有效且常常无法访问的。在吸毒期间，个体暴露于环境线索或施用滥用毒品的环境。强大的药物提示或上下文偏好的发展加速了从间歇性药物使用到药物成瘾的过渡。未来接触这些相同的线索会引起寻求行为的条件，并通过关联学习过程复发。该建议研究了神经生物学机制和治疗方法，以增强这些条件药物反应的灭绝。我们提出的临床前研究研究了条件鸦片奖励（COR）的机制及其灭绝，并测试了C57BL/6小鼠中新型的药理和行为灭绝学习方法。 先前的研究表明，反复给药会改变与成瘾相关行为的皮质和边缘区域的突触可塑性。我们假设用吗啡重复调节会产生由动机和认知神经回路中的可塑性介导的COR。我们已经建立了一个鸦片诱导的条件位置偏好（CPP）的模型，在该模型中，可以在无药物环境中重复进行上下文暴露来测量提示和上下文偏好。我们假设COR的灭绝是一个新的学习过程，可导致学习响应的频率或强度降低。假设COR涉及中皮质糖多巴胺神经元（例如前额叶皮层（PFC）和基底外侧杏仁核（BLA））中脑衍生神经营养因子（BDNF）的增加。提出了鸦片成瘾中的可塑性，以涉及BDNF增加树突状刺中蛋白质合成的能力，改变连通性并调节COR灭绝中的长期记忆。我们假设在PFC区域输注BDNF会增强CPP的灭绝，并阻止启动引起的COR恢复。我们假设其他增强BDNF可塑性的药理学方法也会提高灭绝的速率和/或程度，并减少启动引起的CPP的恢复。我们的研究使用组蛋白脱乙酰基酶抑制剂（HDACI）治疗来增强BDNF可塑性，熄灭COR并减少启动引起的COR的重新计算。 我们的目的将检查中洛林比卡胺和前额叶皮质神经元中的BDNF和神经营养性酪氨酸激酶受体（TRKB）受体机制及其灭绝。我们建议检查前额叶皮质BDNF/TRKB信号传导对CPP灭绝及其引发诱导的COR的灭绝的治疗效果。最后，我们建议使用临床上可用的HDACI，丁酸钠和丙戊酸对BDNF进行表观遗传调节的治疗作用，对COR的灭绝和启动引起的COR恢复。这项翻译研究可以直接推动新的药理学和行为方法来扑灭药物提示和成瘾中的情境反应性，并可以为阿片类药物滥用退伍军人的临床试验设计。 公共卫生相关性： 意义 - 使用物质是影响美国2100万人的巨大社会问题。最近的药物滥用发病率最大的增加是非医学使用阿片类止痛药（220万人）。迫切需要滥用鸦片麻醉品的数百万美国人的新型治疗方法。新的非添加性药物治疗方案的发展可以增加提示暴露，动机和认知心理治疗方法。与退伍军人的健康相关 - 滥用阿片类药物止痛药在VA中是一个很大的问题。服务后，将近一半的OEF/OIF退伍军人经历了持续的或新的痛苦。患有疼痛的退伍军人是处方鸦片止痛药，有滥用的风险。该建议研究了使用药理和行为处理的新治疗方法，以扑灭动物模型中的提示反应性。这种方法可以为未来的临床试验提供滥用老兵的临床试验。