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: 10266093
• 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/10266093
• 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; 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.

有战斗经验的退伍军人中创伤后应激障碍（PTSD）的发病率约为20%， 这一比例远远高于一般人群（约3.5%）。此外，40-50%的退伍军人遭受 PTSD也被诊断为物质使用障碍（SUD）。患有PTSD和SUD的患者 更大的药物使用严重程度，并显示出比诊断为PTSD或 只有SUD。这种特殊的需要返回战斗退伍军人在很大程度上是未解决的临床前研究。 PTSD和SUD都有一个共同的DSM-V特征，即环境刺激与 紧张性刺激或药物的使用可以加速紊乱的症状。条件性药物渴望涉及激活 一个包含前额叶皮层和丘脑核的回路，反复使用药物会产生持久的 突触可塑性的变化。此外，药物条件化线索在动物中引起药物寻求 通过在这些突触处诱导瞬时突触可塑性来建立复发模型。我们最近出版了 提出了进一步的新数据，即大鼠单次急性束缚应激可产生长期（>3周） 与成瘾药物产生的变化相平行的突触变化。总体 我们的假设是，预测压力或药物输送的线索使用相同的皮质类固醇 引起药物寻求和条件性应激反应的机制，这些机制是 合并创伤后应激障碍和SUD 大麻是退伍军人最广泛滥用的成瘾药物之一。我们最近开发了一个 使用两种成分的组合在大鼠中进行大麻自我给药和线索诱导的药物寻找 大麻、四氢大麻酚（THC）和大麻二酚（CBD）。我们建议使用THC+CBD自- 管理和恢复药物寻求与急性约束压力相结合，以评估大麻 使用和条件应激相互作用，通过突触可塑性，促进应激诱导的药物 寻找我们的研究将利用最近的发现，表明量化突触的变化， 典型的突触前和突触后不足以理解药物线索产生的瞬时可塑性。 因此，我们还将量化围绕细胞的富含蛋白质的细胞外基质（ECM）中的信号传导。 突触，以及突触周围星形胶质细胞过程的变化，这些过程通过突触传递调节突触传递。 邻近突触间隙的蛋白质的模式化表达。这四个突触区室合在一起 称为四分突触。 三个拟议的具体目标将按顺序进行。目标1描述了行为和 条件应激的突触效应，使用应激反应的防御性埋藏模型， 应激反应和四分突触可塑性测量之间的相关性有待评估。目的2 使用目标1中收集的信息来研究条件应激与 THC+CBD的使用和寻求。条件压力将用于恢复THC+CBD寻求，我们将 将药物寻求的强度与四分突触可塑性的测量进行比较。最后，在目标3中， 奋进防止条件压力和大麻使用之间的相互作用，通过操纵关键 调节四方突触可塑性的蛋白质，包括星形胶质细胞谷氨酸转运蛋白（GLT-1）和 催化突触可塑性信号的特定基质金属蛋白酶。通过完成这些 具体的目的，我们希望确定重叠的大脑回路和细胞机制之间的条件 压力和大麻寻求，可以在未来的研究中探索作为药物治疗的网站 干预治疗高发病率的创伤后应激障碍和共病SUDs在我们返回的战斗退伍军人。