L-Type Calcium Channel Mechanisms Mediating Comorbid Substance Use and Mood Disorders

L 型钙通道机制介导共病药物使用和情绪障碍

• 批准号: 10454914
• 负责人: Nii A Addy
• 金额: $ 37.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454914
• 关键词: Abstinence; Address; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Attenuated; Behavior; Behavioral; Bipolar Disorder; Brain; Calcium Channel Blockers; Chronic; Chronic stress; Clinical; Clinical Trials; Cocaine; Cocaine Dependence; Cues; Data; Disease; Dopamine; Electrochemistry; Exposure to; Female; Foundations; Future; Genes; Goals; High Prevalence; Human; Individual; Intravenous; Investigation; Isradipine; Knowledge; L-Type Calcium Channels; Laboratories; Major Depressive Disorder; Mediating; Mental Depression; Mental Health; Mood Disorders; Moods; Nucleus Accumbens; Pathway interactions; Periodicity; Pharmaceutical Preparations; Phenotype; Pilot Projects; Rattus; Regulation; Research; Rewards; Rodent; Rodent Model; Role; Scanning; Self Administration; Signal Transduction; Social Interaction; Stress; Substance Use Disorder; Substance abuse problem; Sucrose; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Ventral Tegmental Area; Work; antidepressant effect; associated symptom; behavioral pharmacology; behavioral response; cocaine exposure; cocaine self-administration; comorbidity; disorder risk; drug abstinence; drug of abuse; drug seeking behavior; gain of function mutation; improved; in vivo; inhibitor; male; mesolimbic system; mouse model; neurobiological mechanism; neuropsychiatric disorder; novel; novel therapeutic intervention; pre-clinical; risk variant; social; social deficits; substance use; therapeutic target; therapeutically effective; tool

Individuals with substance use disorders (SUDs) have a higher prevalence of mood and anxiety disorders, and those with mood disorders also have a higher prevalence for SUDs. Periods of drug abstinence are also associated with increased irritability, heightened anxiety, and increased mood disorder symptoms. Further, repeated exposure to either drugs of abuse or stress is associated with mood-related disorders. Thus, the comorbidity between substance abuse and mood disorders is an ongoing challenge for the field. There is a need for both improved understanding of mechanisms mediating this comorbidity and a need for novel and effective therapeutic targets. Research continues to reveal overlapping mechanisms, notably in brain reward pathways, mediating both SUDs and mood-related disorders. In humans, L-type calcium channel (LTCC) genes have been identified as candidate risk genes for cocaine dependence, major depressive disorder, and heightened anxiety. In rodent models, we have found that activation of L-type calcium channels (LTCCs) in the ventral tegmental area (VTA) enhances cocaine-related, depression-like, anxiety-like, and anhedonic behavior, while also inducing social deficits. We have also found that LTCC blockade leads to decreased drug-seeking behavior via regulation of dopamine signaling in the nucleus accumbens (NAc). However, the field still lacks in depth understanding of LTCC mechanisms in neuropsychiatric disorders. More specifically, there is very limited understanding of LTCC mechanisms mediating depression and anxiety-related phenotypes induced by exposure to drugs of abuse or chronic stress – represent a gap in scientific knowledge. Our preliminary findings have revealed that LTCC blockade in cocaine abstinent or chronic stress exposed rats induces anxiolytic-like and antidepressant-like effects. In the current proposal, we will integrate intravenous drug self- administration and chronic unpredictable stress (CUS) paradigms with behavioral pharmacology and in vivo electrochemistry (voltammetry) in male and female rats to: 1) Determine whether LTCC blockade produces anxiolytic-like and antidepressant-like effects and promotes social interaction during cocaine abstinence, via regulation of DA signaling and, 2) Determine whether LTCC blockade attenuates the anxiogenic and anhedonic effects, and the social interaction deficits, of CUS. In this proposal, we will identify the underlying mechanisms by which LTCC blockade may serve as a novel therapeutic intervention to alleviate mood disorder symptoms associated with repeated exposure to cocaine or stress.

患有物质使用障碍(SODS)的人有更高的情绪和焦虑症患病率，并且 那些有情绪障碍的人也有更高的肥皂泡患病率。戒毒期也是 伴随着易怒、焦虑和情绪障碍症状的增加。此外， 反复接触滥用或压力药物与情绪相关障碍有关。因此， 药物滥用和情绪障碍之间的共病是该领域持续存在的挑战。有一个 既需要更好地了解调解这种共病的机制，也需要有新的和 有效的治疗靶点。研究继续揭示重叠的机制，特别是在大脑奖励方面 途径，调节肥皂水和情绪相关的疾病。人的L型钙通道 基因已被确定为可卡因依赖、严重抑郁障碍和 高度焦虑。在啮齿动物模型中，我们发现了L型钙通道(LTCCs)的激活。 腹侧被盖区(VTA)增强了可卡因相关的、抑郁样、焦虑样和非享乐性行为， 同时也会导致社会赤字。我们还发现，LTCC封锁导致寻求毒品的减少 伏隔核(NAC)中多巴胺信号的调节。然而，该领域仍然缺乏 深入了解神经精神障碍的LTCC机制。更具体地说，有非常多的 对LTCC机制介导的抑郁和焦虑相关表型的认识有限 接触滥用药物或慢性压力--代表着科学知识的差距。我们的预赛 研究结果表明，在可卡因戒断或慢性应激暴露的大鼠中阻断LTCC可诱导 抗焦虑和抗抑郁药样作用。在目前的提案中，我们将整合静脉注射药物的自我 用药和慢性不可预测应激(CUS)范式与行为药理学和活体研究 在雄性和雌性大鼠身上进行电化学(伏安法)以确定LTCC阻滞剂是否产生 在可卡因戒断期间，类焦虑和类抗抑郁药的作用和促进社会互动，通过 调节DA信号和，2)确定LTCC阻断是否减弱焦虑性和 CUS的非享乐效应和社会互动缺陷。在这项提案中，我们将确定潜在的 LTCC阻断可作为缓解情绪障碍的一种新的治疗干预机制 与反复接触可卡因或压力有关的症状。