Characterization of alcohol interoceptive effects following predator odor exposure: relevance to PTSD

捕食者气味暴露后酒精内感受效应的表征：与 PTSD 的相关性

• 批准号: 10665399
• 负责人: JOYCE BESHEER
• 金额: $ 38.05万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-12 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665399
• 关键词: Alcohol consumption; Alcohols; Anterior; Attenuated; Beds; Behavior; Behavioral; Caring; Corticosterone; Exposure to; Feces; Funding; Gene Expression; Glutamates; Immobilization; Individual; Individual Differences; Literature; Measures; Mental disorders; Messenger RNA; Metabotropic Glutamate Receptors; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Nucleus Accumbens; Odors; Pathology; Pathway interactions; Pharmacotherapy; Phenotype; Post-Traumatic Stress Disorders; Pre-Clinical Model; Procedures; Rattus; Receptor Gene; Rodent Model; Self Administration; Signal Transduction; Stress; Subgroup; System; Systems Development; Testing; Therapeutic; Time; Trauma; alcohol comorbidity; alcohol effect; alcohol sensitivity; alcohol use disorder; antagonist; conditioning; drinking; drug discrimination; experience; experimental study; foxes; genetic approach; high risk; innovation; interest; neurophysiology; pre-clinical; prevent; receptor; receptor expression; response; stress reactivity; stressor; traumatic event

Project Summary Individuals who suffer from post-traumatic stress disorder (PTSD) are often at higher risk for developing comorbid alcohol use disorder (AUD). Studying individual differences in response to stress is important as not everyone who experiences trauma or witnesses a traumatic event develops PTSD. In preclinical models, exposure to the scent of a predator is commonly used for the study of PTSD-like phenotypes. During the current funding period and in this renewal we use exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) a synthetically derived component of fox feces as the predator odor stressor. We find individual differences in stress reactivity specifically in the engagement of digging in the bedding and immobility behavior during the TMT exposure. While most rats engage primarily in immobility behavior (TMT-1 subgroup), we find a subset of rats engage in a high degree of digging behavior and less immobility (TMT-2 subgroup). This TMT-2 subgroup also shows heightened corticosterone in response to TMT, persistent escalation in alcohol self-administration, and increased TMT- contextual conditioning whereas rats in the TMT-1 subgroup do not. Moreover, while several factors contribute to alcohol drinking, the interoceptive effects associated with drinking are important to study as these are a key part of the drinking experience and can drive ongoing drinking. Further, dysregulation of interoceptive processing is a common feature in several mental health disorders, including PTSD. As such, it is important to consider that escalations in alcohol drinking that emerge following a stressor exposure, may be related to changes in sensitivity to the interoceptive effects of alcohol. Therefore, it is highly significant that we find potentiated sensitivity to the interoceptive effects of alcohol (as measured in a Pavlovian drug discrimination procedure) 2 weeks after TMT exposure, driven by the TMT-2 subgroup. We also find changes in GABAA and NMDA receptor gene expression, primary components of alcohol interoceptive effects, in the anterior insular cortex (aIC) and the nucleus accumbens core (AcbC), key circuitry that we have identified as underlying alcohol interoceptive effects. Lastly, there is a growing body of PTSD literature implicating dysregulated glutamatergic systems in PTSD pathology. We find that treatment with a metabotropic glutamate receptor subtype 3 (mGlu3) negative allosteric modulator (NAM) prior to TMT exposure attenuates some of the adaptations in GABAA and NMDA receptors. Overall, we hypothesize that 1) decreased activity of aICAcbC projections influenced by changes in GABAA and NMDA receptor expression, drive potentiated sensitivity to alcohol 2 weeks after TMT exposure, and 2) that mGlu3 signaling during TMT exposure contributes to these lasting changes. These innovative studies will allow for a broader understanding of the consequences of stressor exposure on alcohol interoceptive effects, as this can lead to a better understanding of interoceptive processing in PTSD, which may influence alcohol drinking.

项目概要 患有创伤后应激障碍 (PTSD) 的人通常面临更高的合并症风险 研究对压力反应的个体差异很重要，因为并非每个人都如此。 在临床前模型中，经历创伤或目睹创伤事件的人会患上创伤后应激障碍（PTSD）。 在当前资助期间，捕食者的气味通常用于研究创伤后应激障碍（PTSD）样表型。 在此更新中，我们使用了 2,5-二氢-2,4,5-三甲基噻唑啉 (TMT) 的暴露，这是一种合成衍生的物质 我们发现狐狸粪便的成分作为捕食者气味应激源的个体差异。 特别是在 TMT 暴露期间的挖掘床上用品和不动行为。 大多数大鼠主要从事不动行为（TMT-1 亚组），我们发现一部分大鼠从事高水平行为 挖掘行为的程度和较少的不动性（TMT-2 亚组） 该 TMT-2 亚组也表现出疲惫。 皮质酮对 TMT 的反应、自我饮酒持续增加以及 TMT 增加 此外，虽然有几个因素起作用，但 TMT-1 亚组的大鼠则不然。 对于饮酒来说，研究与饮酒相关的内感受效应很重要，因为它们是关键 饮酒体验的一部分，并可能导致持续饮酒。此外，内感受处理失调。 这是包括创伤后应激障碍（PTSD）在内的多种精神健康疾病的常见特征，因此，重要的是要考虑到这一点。 暴露于压力源后饮酒量的增加可能与敏感性的变化有关 因此，我们发现对酒精的敏感性增强是非常重要的。 TMT 后 2 周酒精的内感受效应（按照巴甫洛夫药物歧视程序测量） 由 TMT-2 亚组驱动的暴露，我们还发现 GABAA 和 NMDA 受体基因表达的变化， 酒精内感受作用的主要成分，位于前岛叶皮质 (aIC) 和细胞核 伏隔核（AcbC），我们确定其为潜在的酒精内感受效应的关键电路。 越来越多的 PTSD 文献表明 PTSD 病理学中谷氨酸能系统失调。 我们发现用代谢型谷氨酸受体亚型 3 (mGlu3) 负变构调节剂治疗 (NAM) 在 TMT 暴露之前减弱了 GABAA 和 NMDA 受体的一些适应性。 认为 1) aICAcbC 预测的活性降低受 GABAA 和 NMDA 变化的影响 受体表达，在 TMT 暴露后 2 周驱动对酒精的敏感性增强，以及 2) mGlu3 TMT 暴露期间的信号传导有助于这些持久的变化。这些创新研究将允许 更广泛地了解压力源暴露对酒精内感受效应的影响，因为这可以 有助于更好地理解创伤后应激障碍（PTSD）的内感受处理，这可能会影响饮酒。