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.

经历过战斗的退伍军人中创伤后应激障碍 (PTSD) 的发生率约为 20%， 这个比例远高于一般人群（~3.5%）。 Moreover, 40-50% of Veterans suffering PTSD 也被诊断为物质使用障碍 (SUD)。 Patients with comorbid PTSD and SUDs have 与诊断为 PTSD 或 PTSD 的患者相比，吸毒严重程度更高，治疗效果更差 仅 SUD。临床前研究很大程度上没有解决退伍军人返回的这种特殊需求。 PTSD 和 SUD 具有 DSM-V 的共同特征，即环境刺激与 压力源或药物使用可能会引发该疾病的症状。 Conditioned drug cravings involve activation of 包含前额皮质和伏隔核的回路，反复使用药物会产生持久的效果 changes in synaptic plasticity in the accumbens.此外，药物条件信号会引发动物寻求药物 通过在这些突触处诱导瞬时突触可塑性来建立复发模型。 We recently published and 提供了进一步的新数据，表明大鼠的单次急性约束应激会产生持久的（> 3周） 伏隔核突触的变化与成瘾药物产生的变化相似。首要的 我们提案中的假设是，预测压力或药物输送的线索采用相同的伏隔皮质 引发药物寻求和条件应激反应的机制，以及这些机制的基础 共病 PTSD 和 SUD。 大麻是退伍军人最广泛滥用的成瘾药物之一。 We recently developed a model of 使用两种成分组合的大鼠的大麻自我给药和提示诱导药物寻找 大麻、9-四氢大麻酚 (THC) 和大麻二酚 (CBD)。 We propose to use THC+CBD self- 管理和恢复药物寻求结合急性约束压力来评估大麻如何 使用和条件应激通过伏隔核突触可塑性相互作用，促进应激诱导药物 寻求。我们的研究将利用最近的发现，表明量化突触变化 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，以及通过调节突触传递的突触周围星形胶质细胞过程的变化 突触间隙附近蛋白质的模式化表达。 Together, these four synaptic compartments are referred to as the tetrapartite synapse. 拟议的三个具体目标将依次实施。 Aim 1 characterizes the behavioral and 使用压力反应的防御性埋藏模型来研究条件压力的突触效应，这将允许 评估应激反应与四方突触可塑性测量之间的相关性。目标2 使用目标 1 中获得的信息来研究条件压力和条件压力之间的相互作用 THC+CBD 使用和寻求。条件压力将用于恢复 THC+CBD 寻求，我们将 将药物寻找的强度与四方突触可塑性的测量进行比较。最后，在目标 3 中，我们 努力通过操纵关键来防止条件压力和大麻使用之间的相互作用 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。 Through completion of these 具体目标是，我们期望识别条件反射之间重叠的大脑回路和细胞机制 压力和大麻寻求可以在未来的研究中作为药物治疗场所进行探索 治疗回国退伍军人中高发 PTSD 和共病 SUD 的干预措施。