Interoceptive processing and alcohol relapse-like behavior

内感受处理和酒精复吸样行为

• 批准号: 10313766
• 负责人: Dennis Lovelock
• 金额: $ 7.31万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313766
• 关键词: Abstinence; Alcohol consumption; Alcohol dependence; Alcohols; Anterior; Area; Attention; Behavior; Behavioral; Behavioral Model; Bilateral; Blood Vessels; Brain; Brain region; Cannulas; Celiac Plexus; Chemosensitization; Clozapine; Coupled; Cues; Data; Eating; Environment; Esthesia; Exposure to; Extinction (Psychology); Feeling; Female; Goals; Heart; Heart Rate; High Prevalence; Implant; Individual; Infusion procedures; Insula of Reil; Lead; Learning; Ligands; Liquid substance; Long-Evans Rats; Measures; Microinjections; Midline Thalamic Nuclei; Motivation; Nucleus solitarius; Organ; Oxides; Perception; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Play; Procedures; Process; Rattus; Recovery; Relapse; Research; Reuniens Thalamic Nucleus; Rewards; Role; Self Administration; Sensory; Stimulus; Stomach; Structure of rhomboidal nucleus of thalamus; Technology; Testing; Training; Vagus nerve structure; Viral; Virus; Visceral; Work; alcohol effect; alcohol relapse; alcohol seeking behavior; alcohol use disorder; alcohol use initiation; base; craving; design; designer receptors exclusively activated by designer drugs; drinking; drug craving; experimental study; implantation; insight; male; multimodality; neural circuit; response; transmission process

Abstract Stimuli associated with drugs have a powerful influence over the behavior. Many studies have established the ability of drug-related cues and contexts to induce relapse after a period of abstinence. Importantly, exposure to drug-associated cues can also produce specific interoceptive effects related to drug craving, such as feelings of increased tension, jitteriness, and changes in heart rate. However few studies have examined how interoceptive responses to these cues can then become drivers of behavior. The current experiments propose to use a highly relevant behavioral model of context-induced reinstatement combined with manipulation of neural circuitry likely to be involved in interoceptive perception using viral chemogenetic technology. In these experiments, rats will be trained to self-administer alcohol in a specific context that will become associated with the drug. Subsequently, rats will undergo extinction in a separate context where responses do not result in delivery of alcohol. Then, rats will be tested in the original alcohol-associated context in a two-phase reinstatement procedure consisting of a seeking phase where lever presses have no programmed consequence (i.e., seeking phase) and then a re-initiation of self-administration phase where responses will again be rewarded (i.e., re-initiation of self-administration phase). This design allows for examination of multiple factors that can contribute to relapse. Using this design, Aim 1 will determine the functional role of the nucleus reuniens (RE) to anterior insula (AI) projection with virus infusions of Gi-coupled hM4Di Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) into the RE followed by implantation of bilateral cannulae targeting the AI. This circuit will be silenced on the reinstatement test day by activating the Gi DREADDs via delivery of the ligand clozapine-N-oxide (CNO) into the AI. I hypothesize that silencing this circuit will disrupt processing of interoceptive cues that contribute to alcohol seeking and will increase responding upon re-initiation of self-administration. Aim 2 will use the same viral strategy to silence the projection from the nucleus of the solitary tract (NTS) to the RE. I hypothesize that Gi DREADD activation in this circuit will both disrupt interoceptive cues that contribute to alcohol seeking behavior and re-initiation of alcohol self-administration. Altogether, the experiments in this application seek to demonstrate that silencing of brain circuits likely to be involved in the processing of peripheral body state information disrupts use of this information as an interoceptive cue that contributes to alcohol use disorder and relapse.

抽象的 与药物相关的刺激对行为有很大的影响。许多研究已经确定 戒毒一段时间后，与药物相关的线索和环境诱发复吸的能力。重要的是曝光度 与药物相关的线索也可以产生与药物渴望相关的特定内感受效应，例如 紧张、不安和心率变化的感觉。然而很少有研究探讨如何 对这些线索的内感受反应可以成为行为的驱动因素。目前的实验提出 使用情境诱导恢复的高度相关行为模型，并结合操纵 使用病毒化学遗传学技术可能参与内感受知觉的神经回路。在这些 实验中，老鼠将被训练在特定的环境中自我饮酒，这将与 药物。随后，老鼠将在一个单独的环境中经历灭绝，在该环境中，反应不会导致 酒精的输送。然后，将在最初的酒精相关环境中对大鼠进行两阶段测试 恢复程序包括一个寻找阶段，其中压杆没有编程 结果（即寻求阶段），然后重新启动自我管理阶段，其中响应将 再次获得奖励（即重新启动自我管理阶段）。该设计允许检查 多种因素可能导致复发。使用这种设计，目标 1 将确定 通过 Gi 耦合 hM4Di Designer 的病毒输注，将核团聚 (RE) 投影到前岛叶 (AI) 由设计药物 (DREADD) 独家激活的受体进入 RE，然后植入 针对 AI 的双侧插管。该电路将在恢复测试日通过激活 Gi DREADDs 通过将配体氯氮平-N-氧化物 (CNO) 递送至 AI 中。我假设沉默这个 电路会扰乱有助于寻找酒精的内感受线索的处理，并会增加 重新开始自我管理后做出反应。目标 2 将使用相同的病毒策略来压制 从孤束核（NTS）到 RE 的投影。我假设 Gi DREADD 激活在 该回路将破坏内感受线索，从而导致寻求酒精的行为和重新启动 酒精自我管理。总而言之，本申请中的实验旨在证明沉默 可能参与外周身体状态信息处理的大脑回路扰乱了这种信息的使用 信息作为内感受线索，导致酒精使用障碍和复发。