Examination of novel brain regional involvement in modulating sensitivity to alcohol

检查新的大脑区域参与调节酒精敏感性

• 批准号: 9301276
• 负责人: Anel Ariana Jaramillo
• 金额: --
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-08 至 2017-06-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301276
• 关键词: Alcohol consumption; Alcohols; Behavior; Behavioral inhibition; Brain; Brain region; Clinical; Clinical Research; Cues; Data; Discrimination; Drug abuse; Drug usage; Experimental Designs; Feedback; Goals; Human; Income; Long-Evans Rats; Mediating; Methods; Midline Thalamic Nuclei; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Organism; Pharmaceutical Preparations; Play; Process; Rattus; Relapse; Role; Satiation; Signal Transduction; Site; Stimulus; Techniques; Testing; Tissues; Training; Water; Work; alcohol behavior; alcohol cue; alcohol effect; alcohol pharmacology; alcohol sensitivity; brain circuitry; designer receptors exclusively activated by designer drugs; drug discrimination; drug of abuse; experimental study; flexibility; innovation; male; neural circuit; novel; pre-clinical; preclinical study; relating to nervous system; rhomboid

PROJECT SUMMARY/ABSTRACT All drugs of abuse produce unique interoceptive/subjective (i.e., discriminative stimulus) effects that can impact drug-taking, seeking, and relapse in both clinical and preclinical studies. However, the neural circuitry modulating the interoceptive effects of alcohol has yet to be established. The nucleus accumbens core (AcbC), a region known to mediate alcohol-related behaviors, also plays a central role in modulating the discriminative stimulus effects of alcohol. Therefore, to begin to establish the circuitry modulating the interoceptive effects of alcohol, two brain regions with projections to the AcbC will be the focus of the proposed studies: the insular cortex (IC) and the rhomboid/reuniens ventral midline thalamic nuclei (RhRe). Despite the implicated role of the IC in processing interoceptive cues and responding to alcohol-related cues, its functional role in modulating alcohol-induced interoceptive effects has not been investigated to date. Additionally, the RhRe are proposed to modulate inhibition, behavior flexibility, and motivation, but their role in modulating any drug-related behaviors has yet to be determined. However, our preliminary data demonstrate that chemogenetic inactivation of the IC increases sensitivity to alcohol and pharmacological inactivation of IC and RhRe (independently) results in partial “alcohol-like” interoceptive effects, thus implicating a functional role for the IC and RhRe in modulating the discriminative stimulus effects of alcohol. Therefore, by investigating the two novel brain regions (IC and RhRe) and their projections to the AcbC, this application proposes to investigate the neural circuitry underlying alcohol-induced interoceptive states. Using drug discrimination methods, rats will be trained to discriminate alcohol vs. water, and we will chemogenetically inactivate the brain regions and their specific incoming AcbC projections to examine whether sensitivity to alcohol is altered. Thus, experiments in Aim 1 will determine whether IC and its projections to the AcbC modulate the discriminative stimulus effects of alcohol. Aim 2 will use a similar approach to determine the role of RhRe and its projections to the AcbC. Together these experiments will demonstrate a functional role for two novel brain regions in modulating the interoceptive effects of alcohol, while identifying potential AcbC-related neural circuitry. By conducting these experiments in parallel, this innovative approach has the ability to inform the alcohol field of regions not previously implicated or understudied while demonstrating the importance and neurobiology underlying alcohol interoceptive states/internal cues, thus helping bridge the clinical and preclinical fields.

项目总结/摘要 所有滥用药物都会产生独特的内感受性/主观性（即，歧视性刺激）影响 临床和临床前研究中的药物服用、寻求和复发。然而，神经回路 调节酒精的内感受性作用还有待建立。核心核（AcbC）， 一个已知调节酒精相关行为的区域，也在调节辨别性行为中起着核心作用。 酒精的刺激作用。因此，为了开始建立调节内感受性效应的电路， 酒精，两个大脑区域的预测，以AcbC将是重点的拟议研究：岛 皮质（IC）和菱形/连合腹侧中线丘脑核（RhRe）。尽管有牵连的作用， IC在处理内感受性线索和对酒精相关线索的反应中的作用， 迄今尚未研究酒精诱导的内感受性效应。此外，RhRe被提议用于 调节抑制，行为灵活性和动机，但它们在调节任何药物相关行为中的作用 尚未确定。然而，我们的初步数据表明，IC的化学失活 增加对酒精的敏感性，IC和RhRe（独立）的药理学失活导致 部分“酒精样”内感受性效应，因此暗示IC和RhRe在调节 酒精的辨别刺激效应。因此，通过研究两个新的大脑区域（IC和 RhRe）和它们到AcbC的投射，本申请提出研究潜在的神经回路。 酒精诱导的内感受状态使用药物辨别方法，将训练大鼠辨别 酒精与水，我们将化学遗传学的大脑区域和他们的特定传入AcbC 预测以检查对酒精的敏感性是否改变。因此，目标1中的实验将确定 IC及其对AcbC的投射是否调节酒精的辨别性刺激效应。目标2将 使用类似的方法来确定RhRe的作用及其对AcbC的预测。综合这些 实验将证明两个新的大脑区域在调节内感受性中的功能作用。 酒精的影响，同时确定潜在的AcbC相关的神经回路。通过进行这些实验， 与此同时，这种创新的方法有能力告知酒精领域以前没有涉及的地区 或者在证明酒精内感受性的重要性和神经生物学基础时， 状态/内部线索，从而帮助弥合临床和临床前领域。