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

项目摘要 患有创伤后应激障碍（PTSD）的人通常有更高的风险患上共病。 酒精使用障碍（AUD）研究个体在应对压力时的差异很重要，因为不是每个人都 经历创伤或目睹创伤性事件的人会患上创伤后应激障碍。在临床前模型中， 捕食者的气味通常用于PTSD样表型的研究。本供资期间 在这次更新中，我们使用暴露于2，5-二氢-2，4，5-三甲基噻唑啉（TMT）， 狐狸粪便的成分作为捕食者气味应激源。我们发现压力反应的个体差异 特别是在TMT暴露期间，在垫层中挖掘和不动行为的参与。而 大多数大鼠主要从事不动行为（TMT-1亚组），我们发现一个子集的大鼠从事高 挖掘行为的程度和较少的不动性（TMT-2亚组）。这一TMT-2亚组也显示出 皮质酮对TMT的反应，酒精自我管理的持续升级，以及TMT增加， 而TMT-1亚组的大鼠则没有。此外，虽然有几个因素有助于 与饮酒有关的内感受性影响很重要，因为这些是研究饮酒的关键。 这是饮酒体验的一部分，可以推动持续的饮酒。此外，内感受性处理的失调 是包括创伤后应激障碍在内的几种精神疾病的共同特征。因此，必须考虑到， 压力源暴露后出现的饮酒升级可能与敏感性的变化有关 酒精的内感受性影响因此，非常重要的是，我们发现了对 TMT后2周酒精的内感受性效应（如在巴甫洛夫药物辨别程序中测量的） 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， 酒精内感受效应的主要成分，在前岛皮质（aIC）和核中 AcbC，我们已经确定为潜在的酒精内感受性效应的关键电路。最后， 越来越多的PTSD文献表明PTSD病理学中的神经递质系统失调。 我们发现用代谢型谷氨酸受体亚型3（mGlu 3）负变构调节剂治疗 (NAM)在TMT暴露之前，GABAA和NMDA受体的一些适应减弱。总的来说，我们 假设1）受GABAA和NMDA变化影响，aIC和AcbC投射活性降低 TMT暴露后2周，受体表达，驱动对酒精的敏感性增强，2）mGlu 3 TMT暴露期间的信号传导有助于这些持久的变化。这些创新的研究将使 更广泛地理解压力源暴露对酒精内感受性影响的后果，因为这可以 导致更好地理解PTSD中的内感受性处理，这可能会影响饮酒。

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.