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Cannabinoids for Posttraumatic Stress Disorder and Alcohol Use

大麻素治疗创伤后应激障碍和饮酒

基本信息

批准号：
10179503
负责人：
Shane Alan Perrine
金额：
--
依托单位：
JOHN D DINGELL VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179503
关键词：
2-arachidonylglycerol Address Affect Afghanistan Agonist Alcohol consumption Alcoholism Alcohols Amino Acids Animals Anxiety Behavior Behavioral Brain region CNR1 gene Calcium Cannabinoids Chronic Corpus striatum structure Data Diagnosis Disease Disease model Disinhibition Drug Receptors Endocannabinoids Energy Metabolism Ethanol Exposure to Functional Magnetic Resonance Imaging Functional disorder GABA Receptor Glutamate Receptor Glutamates Habits Health Human Hyperactivity Imaging Techniques Impairment Individual Intervention Iraq Knowledge Ligands Long-Term Effects Magnetic Resonance Imaging Magnetism Manganese Measures Mediating Medical Military Personnel Modeling Molecular Molecular Neurobiology Morphology N-acetylaspartate Neurites Neuronal Plasticity Neurons Neurotransmitter Receptor Neurotransmitters Outcome Outcome Measure Pathway interactions Patient Care Patients Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Post-Traumatic Stress Disorders Prevalence Protons Radial Rattus Receptor Activation Receptor Signaling Recovery Regulation Rehabilitation therapy Rewards Risk Rodent Model Role Spectrum Analysis Stress Structure Symptoms System Techniques Testing Therapeutic Therapeutic Intervention Time Vertebral column Veterans active duty activity marker addiction alcohol use disorder anandamide anxiety-like behavior arm associated symptom base behavior measurement brain behavior cannabinoid receptor combat zone comorbidity drinking behavior efficacy evaluation functional outcomes gamma-Aminobutyric Acid imaging modality improved in vivo innovation longitudinal design methanandamide military veteran molecular marker multimodality neurochemistry neuroimaging neurotransmission novel preclinical study receptor receptor expression receptor function rehabilitation strategy relating to nervous system response stress reactivity targeted treatment traumatic stress welfare

项目摘要

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.]

项目摘要-摘要在阿富汗和伊拉克的作战行动，创伤后应激障碍（PTSD）的退伍军人。最近的数据表明，那些患有PTSD的人酒精中毒和酒精使用障碍（AUD）的发生率较高。PTSD+AUD的独特效果与单独的创伤后应激障碍相比，在VA，军事和民用医疗设施的挑战。越来越重要的是，患有PTSD+AUD共病的退伍军人的症状与AUD或PTSD相关症状的比较在康复期间，一种机制最近成为焦点，以解释共病PTSD+AUD的复合效应是受损的皮质激活，导致自上而下的功能丧失，纹状体的控制，这是一个在成瘾性疾病（如AUD）中控制奖励和习惯反应的区域。令人惊讶的是，到目前为止，很少有临床前研究来评估PTSD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。在本申请中，将通过检查脑梗死患者的纹状体激活来解决这一知识缺口。共病PTSD+AUD，使用PTSD的啮齿动物模型。将在多个水平上评估纹状体激活，包括兴奋性/抑制性神经传递、树突结构、神经激活和纹状体的标志物，中介行为PTSD和AUD的一个共同机制涉及大麻素系统，证据表明大麻素配体对这些疾病具有治疗潜力。的实力应用是从受体表达和激活到纹状体功能的综合分析，行为测量和使用新的成像方式来检查脑的纵向进展，行为关系。此外，使用新型大麻素能药物的康复干预，如甲睾酮将用作PTSD+AUD共病的预防相关治疗。我们假设PTSD+AUD的组合会加剧行为和分子水平的终点，兴奋性/抑制性神经递质和受体水平的功能评估，树突状细胞形态学、神经元可塑性和纹状体激活，将通过神经治疗干预逆转。我们将使用以下特定目的来检验这一假设：1）评估共病的影响 PTSD+AUD对纹状体依赖性行为[包括饮酒，习惯行为和焦虑]，神经突形态学，兴奋性/抑制性神经传递的标志物，[和大麻素系统的成分] 与单独的任何一种情况相比，2）量化共病PTSD+AUD对纹状体的长期影响，神经递质水平（神经化学）和神经激活（功能）使用新的磁共振与单独的任一种情况相比，在体内以纵向方式使用成像技术。[In这两个目标我们将评估基于大麻素的神经治疗治疗改善/恢复细胞的能力，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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

D-578, an orally active triple monoamine reuptake inhibitor, displays antidepressant and anti-PTSD like effects in rats.

DOI：
10.1016/j.ejphar.2019.172632
发表时间：
2019-11-05
期刊：
EUROPEAN JOURNAL OF PHARMACOLOGY
影响因子：
5
作者：
Dutta, Aloke K.;Santra, Soumava;Harutyunyan, Arman;Das, Banibrata;Lisieski, Michael J.;Xu, Liping;Antonio, Tamara;Reith, Maarten E. A.;Perrine, Shane A.
通讯作者：
Perrine, Shane A.

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder.

DOI：
10.3389/fpsyt.2018.00196
发表时间：
2018
期刊：
Frontiers in psychiatry
影响因子：
4.7
作者：
Lisieski MJ;Eagle AL;Conti AC;Liberzon I;Perrine SA
通讯作者：
Perrine SA

Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats.

DOI：
10.1038/s41598-020-74481-3
发表时间：
2020-10-21
期刊：
Scientific reports
影响因子：
4.6
作者：
Chaby LE;Sadik N;Burson NA;Lloyd S;O'Donnel K;Winters J;Conti AC;Liberzon I;Perrine SA
通讯作者：
Perrine SA

Calcium/calmodulin-stimulated adenylyl cyclases 1 and 8 regulate reward-related brain activity and ethanol consumption.

DOI：
10.1007/s11682-018-9856-6
发表时间：
2019-04
期刊：
Brain imaging and behavior
影响因子：
3.2
作者：
Bosse KE;Ghoddoussi F;Eapen AT;Charlton JL;Susick LL;Desai K;Berkowitz BA;Perrine SA;Conti AC
通讯作者：
Conti AC

Editorial: Pre-clinical Models of PTSD.

社论：PTSD 的临床前模型。