Neuroadaptation produced by acute PTSD-like stress create vulnerability for cannabis addiction

急性创伤后应激障碍（PTSD）样压力产生的神经适应导致大麻成瘾的脆弱性

• 批准号: 10477266
• 负责人: Peter W Kalivas
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477266
• 关键词: Acetylcysteine; Acute; Acute Post Traumatic Stress Disorder; Animal Model; Behavioral; Brain; Cannabidiol; Cannabis; Characteristics; Clinical; Cues; DSM-V; Data; Dendritic Spines; Diagnosis; Disease; Drug Delivery Systems; Drug usage; Extinction (Psychology); Extracellular Matrix; Future; General Population; Glutamate Transporter; Glutamates; Incidence; Intervention; Investigation; Life; Matrix Metalloproteinases; Measurement; Measures; Mediating; Metalloproteases; Modeling; Morphology; N-Methylaspartate; Neurologic; Nucleus Accumbens; Odors; Outcome; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Proteins; Publishing; Rattus; Relapse; Research; Self Administration; Severities; Signal Transduction; Site; Stimulus; Stress; Stressful Event; Substance Use Disorder; Symptoms; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic plasticity; Testing; Tetrahydrocannabinol; Training; Treatment outcome; Veterans; addiction; biological adaptation to stress; brain circuitry; combat; combat veteran; comorbidity; conditioning; density; drug craving; experience; improved; innovation; marijuana use; neuroadaptation; neurobiological mechanism; novel; postsynaptic; pre-clinical research; preclinical evaluation; prevent; protein expression; restraint stress; stressor

The incidence of post-traumatic stress disorder (PTSD) among combat-experienced Veterans is ~20%, which is substantially larger than in the general population (~3.5%). Moreover, 40-50% of Veterans suffering PTSD are also diagnosed with substance use disorders (SUDs). Patients with comorbid PTSD and SUDs have greater drug use severity and show poorer treatment outcomes than patients diagnosed with either PTSD or SUDs alone. This special need of returning combat Veterans is largely unaddressed by preclinical research. PTSD and SUDs share in common the DSM-V characteristic that environmental stimuli associated with a stressor or drug use can precipitate symptoms of the disorder. Conditioned drug cravings involve activation of a circuit containing the prefrontal cortex and nucleus accumbens, and repeated drug use produces enduring changes in synaptic plasticity in the accumbens. Also, drug-conditioned cues elicit drug seeking in animal models of relapse by inducing transient synaptic plasticity at these synapses. We recently published and present further new data that a single episode of acute restraint stress in rats produces long-lasting (>3 weeks) changes in accumbens synapses that parallel the changes produced by addictive drugs. The overarching hypothesis in our proposal is that cues predicting stress or drug delivery employ the same cortico-accumbens mechanisms to elicit drug seeking and conditioned stress responding, and that these mechanisms underlie comorbid PTSD and SUDs. Cannabis is among the addictive drugs most widely abused by Veterans. We recently developed a model of cannabis self-administration and cue-induced drug seeking in rats that uses a combination of two constituents of cannabis, 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We propose to use THC+CBD self- administration and reinstated drug seeking in combination with acute restraint stress to evaluate how cannabis use and conditioned stress interact through accumbens synaptic plasticity to promote stress-induced drug seeking. Our investigation will utilize recent discoveries showing that quantifying synaptic changes in the canonical pre- and postsynapse is insufficient to understand the transient plasticity produced by drug cues. Accordingly, we will also quantify signaling in the protein-rich extracellular matrix (ECM) that surrounds the synapse, and changes in perisynaptic astroglial processes that regulate synaptic transmission through the patterned expression of proteins adjacent to the synaptic cleft. Together, these four synaptic compartments are referred to as the tetrapartite synapse. The three proposed Specific Aims will be sequentially engaged. Aim 1 characterizes the behavioral and synaptic effects of conditioned stress using the defensive burying model of stress responding that will allow correlations to be evaluated between stress responding and measures of tetrapartite synaptic plasticity. Aim 2 uses the information garnered in Aim 1 to investigate the interactions between conditioned stress and THC+CBD use and seeking. Conditioned stress will be used to reinstate THC+CBD seeking and we will compare the intensity of drug seeking with measures of tetrapartite synaptic plasticity. Finally, in Aim 3 we endeavor to prevent the interactions between conditioned stress and cannabis use by manipulating key proteins regulating tetrapartite synaptic plasticity, including the astroglial glutamate transporter (GLT-1) and specific matrix metalloproteases that catalytically signal synaptic plasticity. Through completion of these Specific Aims, we expect to identify overlapping brain circuitry and cellular mechanisms between conditioned stress and cannabis seeking that can be explored in future studies as sites of pharmacotherapeutic intervention for treating the high incidence of PTSD and comorbid SUDs in our returning combat Veterans.

经验丰富的退伍军人中创伤后应激障碍（PTSD）的事件约为20％， 比一般人群大得多（约3.5％）。此外，有40％至50％的退伍军人受苦 PTSD还被诊断出患有药物使用障碍（SUDS）。合并症PTSD和SUD的患者患有 比诊断为PTSD或PTSD或 独自一人。临床前研究在很大程度上未能使退伍军人返回战斗退伍军人的特殊需求。 PTSD和SUDS共同具有与A相关的环境刺激的DSM-V特征 压力源或吸毒会导致该疾病的症状。有条件的药物渴望涉及激活 包含前额叶皮层和伏隔核的电路，并重复使用药物会产生持久 伏伏茎突触可塑性的变化。此外，药物条件提示引起的动物寻求药物 在这些突触下引起的瞬态合成可塑性的浮雕模型。我们最近出版了 呈现进一步的新数据，大鼠的急性约束应力发作会产生持久（> 3周） 伏隔突触的变化与加性药物产生的变化平行。总体 我们的提案中的假设是，预测压力或药物输送的提示采用了相同的皮质囊室 引起毒品寻求和有条件压力的机制，这些机制是基础的 合并症PTSD和SUDS。 大麻是退伍军人最广泛滥用的加性药物之一。我们最近开发了一个模型 大麻自给自足和提示引起的药物在大鼠中使用两种构成的组合 大麻，9-四氢大麻酚（THC）和大麻二酚（CBD）我们建议使用THC+CBD自我 施用和恢复药物与急性约束应力结合使用，以评估大麻的方式 使用和条件应力通过声学突触可塑性相互作用，以促进压力诱导的药物 寻求。我们的投资将利用最近的发现，表明量化突触变化 典型的前和后造成的不足以理解药物提示产生的瞬时可塑性。 彼此之间，我们还将量化富含蛋白质的细胞外基质（ECM）中的信号传导 突触，以及通过调节突触传播的直发星形胶质过程的变化 与合成裂缝相邻的蛋白质的图案表达。在一起，这四个合成室是 称为四方突触。 提出的三个特定目标将依次参与。瞄准1个字符的行为和 使用防御性掩埋的压力响应模型对条件应力的突触效应，这将允许 应力反应与四边形突触可塑性的度量之间的相关性。目标2 使用AIM 1中获得的信息来研究条件应力与 THC+CBD使用和寻求。条件应力将用于恢复THC+CBD寻求，我们将 比较寻求药物的强度与四方合成可塑性的测量。最后，在目标3中我们 努力通过操纵钥匙来防止条件压力和大麻使用之间的相互作用 蛋白质的蛋白质恢复四边形突触可塑性，包括星形胶质酸谷氨酸转运蛋白（GLT-1）和 特定的基质金属蛋白酶催化信号合成可塑性。通过完成这些 具体目的，我们希望确定条件之间的重叠脑电路和细胞机制 可以在未来的研究中作为药物治疗部位探索的压力和大麻寻求大麻 在我们的返回战斗退伍军人中，干预治疗PTSD和合并症的高潮事件的干预措施。