Cannabinoids for Posttraumatic Stress Disorder and Alcohol Use

项目摘要-摘要 在阿富汗和伊拉克的战斗行动一直与增加的流行有关 退伍军人的创伤后应激障碍(PTSD)。最近的数据表明，那些患有创伤后应激障碍的人 表现出较高的酒精中毒和酒精使用障碍(AUD)率。创伤后应激障碍+AUD的独特效应 与单纯创伤后应激障碍相比，受影响者的诊断、管理、治疗和康复 在退伍军人管理局、军事和民用医疗设施方面的挑战。认识到这一点变得越来越重要 退伍军人合并PTSD+AUD与AUD或PTSD相关症状的比较 独自一人，在康复期。最近成为焦点的一种机制解释了 合并PTSD和AUD的复合效应是皮质激活受损，导致自上而下的丧失 对纹状体的控制，纹状体是控制成瘾障碍中奖赏和习惯反应的区域，如AUD。 令人惊讶的是，到目前为止，几乎没有临床前研究来评估创伤后应激障碍对神经活动的影响。 纹状体，增加了拟议项目的意义和概念创新。 这一知识差距将在当前的应用中通过检查纹状体激活 PTSD+AUD共病，采用创伤后应激障碍啮齿动物模型。纹状体的激活将在多个水平上进行评估， 包括兴奋性/抑制性神经传递、树突结构、神经激活和纹状体- 居间行为。PTSD和AUD共同的一种机制涉及大麻素系统和 有证据表明，大麻素配体对这些疾病具有治疗潜力。这一点的力量 应用是纹状体功能的综合分析，从受体的表达和激活到 行为测量和使用新的成像模式来检查大脑的纵向发展- 行为关系。此外，使用新型大麻能药物的康复干预措施，例如 甲胺，将被用作与翻译相关的治疗PTSD+AUD的方法。 我们推测，PTSD+AUD的组合将加剧行为和分子方面的 终末，兴奋性/抑制性神经递质和受体水平的功能评估，树突状细胞 形态、神经元可塑性和纹状体激活与任何一种情况单独比较，以及这些缺陷 将通过神经治疗干预逆转。 我们将通过以下具体目标来检验这一假设：1)评估并存疾病的影响 PTSD+AUD对纹状体依赖行为[包括饮酒、习惯行为和焦虑]、轴突的影响 形态、兴奋性/抑制性神经传递的标记物[和大麻素系统的成分] 2)量化PTSD+AUD并存对纹状体的长期影响 用新的磁共振研究神经递质水平(神经化学)和神经激活(功能) 在体内以纵向方式成像的技术与单独使用这两种情况相比。[在这两个目标中 我们将评估以大麻素为基础的神经治疗改善/恢复细胞和 与PTSD+AUD相关的分子缺陷，从而改善基于纹状体的行为和功能。]

Project Summary – Abstract Combat operations in Afghanistan and Iraq have been associated with increased prevalence of posttraumatic stress disorder (PTSD) among veterans. Recent data demonstrate that those with PTSD demonstrate higher rates of alcoholism and alcohol use disorders (AUDs). The unique effects of PTSD+AUD compared to PTSD alone make the diagnosis, management, treatment, and rehabilitation of those affected a challenge in VA, military, and civilian medical facilities. It has become increasingly important to recognize symptoms in Veterans with comorbid PTSD+AUD compared to those symptoms associated with AUD or PTSD alone, in the rehabilitation period. One mechanism to have recently come into focus to explain the compounded effects of comorbid PTSD+AUD is impaired cortical activation that leads to loss of top-down control of the striatum, a region that governs reward and habit responding in addictive disorders, such as AUD. Surprisingly, to date, there have been few preclinical studies to evaluate the impact of PTSD on neuroactivity in the striatum, adding to the significance and conceptual innovation of the proposed project. This knowledge gap will be addressed in the current application by examining striatal activation in comorbid PTSD+AUD, using a rodent model of PTSD. Striatal activation will be evaluated at numerous levels, including markers of excitatory/inhibitory neurotransmission, dendritic structure, neural activation and striatal- mediated behaviors. One mechanism common to both PTSD and AUD involves the cannabinoid system and evidence suggests that cannabinoid ligands have therapeutic potential for these disorders. The strength of this application is the comprehensive analysis of striatal function from receptor expression and activation to behavioral measures and use of novel imaging modalities to examine the longitudinal progression of brain- behavior relationships. In addition, rehabilitative interventions using novel cannabinoidergic drugs, such as methanandamide, will be employed as translationally-relevant therapies for comorbid PTSD+AUD. We hypothesize that the combination of PTSD+AUD will exacerbate behavioral and molecular endpoints, functional assessments of excitatory/inhibitory neurotransmitter and receptor levels, dendritic morphology, neuronal plasticity and striatal activation compared to either condition alone and that these deficits will be reversed by neurotherapeutic intervention. We will test this hypothesis using the following Specific Aims: 1) Evaluate the influence of comorbid PTSD+AUD on striatal-dependent behaviors [including alcohol drinking, habit behavior and anxiety], neurite morphology, markers of excitatory/inhibitory neurotransmission, [and components of the cannabinoid system] compared to either condition alone, 2) Quantify the long-term impacts of comorbid PTSD+AUD on striatal neurotransmitter levels (neurochemical) and neuroactivation (functional) using novel magnetic resonance imaging techniques in a longitudinal manner in vivo compared to either condition alone. [In both of these aims we will evaluate the ability of a cannabinoid-based neurotherapeutic treatment to improve/restore cellular and molecular deficits associated with PTSD+AUD and thereby, to improve striatal-based behaviors and function.]