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

在有战斗经验的退伍军人中，创伤后应激障碍(PTSD)的发生率约为20%。 这一数字大大高于一般人口(约3.5%)。此外，40%-50%的退伍军人遭受 创伤后应激障碍还被诊断为物质使用障碍(SUDS)。患有创伤后应激障碍和肥皂水的患者 与被诊断为创伤后应激障碍或创伤后应激障碍的患者相比，药物使用严重程度更高，治疗结果更差 单独的肥皂水。临床前研究在很大程度上没有解决退伍军人的这种特殊需求。 创伤后应激障碍和肥胖症具有共同的DSM-V特征，即环境刺激与 应激源或药物的使用会引发这种疾病的症状。条件性药物渴求涉及激活 一种包含前额叶皮质和伏隔核的环路，反复使用药物会产生持久的效果 伏隔核突触可塑性的变化。此外，药物条件线索还会在动物身上引发药物寻找 通过在这些突触诱导瞬时突触可塑性来建立复发模型。我们最近出版了和 进一步的新数据表明，大鼠的一次急性束缚应激可持续3周。 伏隔神经突触的变化与成瘾药物产生的变化相似。最重要的是 我们建议的假设是，预测压力或药物传递的信号使用相同的皮质-伏隔神经 诱导药物寻求和条件应激反应的机制，以及这些机制的基础 同时患有创伤后应激障碍和肥皂水。 大麻是退伍军人滥用最广泛的成瘾药物之一。我们最近开发了一种模型 使用两种成分组合的大麻自我给药和线索诱导的大鼠药物寻找 对于大麻，9-四氢大麻酚和大麻二酚。我们建议采用THC+CBD自营 用药和恢复药物寻求结合急性约束应激来评估大麻 使用和条件应激通过伏隔神经突触可塑性相互作用促进应激诱导的药物 寻找。我们的研究将利用最近的发现，表明量化大脑中的突触变化 规范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，我们还将量化围绕着细胞外基质(ECM)的富含蛋白质的信号。 突触，以及突触周围星形胶质细胞过程的变化，这些变化通过 邻近突触裂隙的蛋白质的图案化表达。加在一起，这四个突触间隔是 被称为四部分突触。 提出的三个具体目标将相继实施。目标1描述了行为和 使用应激反应的防御性掩埋模型的条件性应激的突触效应将允许 应激反应和四部分突触可塑性的测量之间的相关性有待评估。目标2 使用在目标1中获得的信息来研究条件性应激和 THC+CBD的使用和寻找。条件性压力将被用来恢复THC+CBD寻找，我们将 将药物寻找的强度与四部分突触可塑性的测量进行比较。最后，在目标3中，我们 努力防止条件应激和大麻使用之间的相互作用 调节四分突触可塑性的蛋白质，包括星形胶质谷氨酸转运体(GLT-1)和 催化突触可塑性的特定基质金属蛋白酶。通过完成这些 特定的目标，我们希望确定重叠的大脑电路和细胞机制之间的条件 压力和寻找大麻，可以在未来的研究中作为药物治疗的场所来探索 我国退伍军人创伤后应激障碍及伴发肥皂水的高发干预。

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.