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: 10266131
• 负责人: Nii A Addy
• 金额: $ 36.77万
• 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/10266131
• 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/antagonist; 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.

物质使用障碍（SUD）患者的情绪和焦虑障碍患病率较高， 那些有情绪障碍的人也有更高的SUD患病率。戒毒期也是 与增加的易怒、增加的焦虑和增加的情绪障碍症状相关。此外，本发明还 反复接触滥用药物或压力与情绪相关的障碍有关。因此 药物滥用和情绪障碍之间的共病是该领域的一个持续挑战。有一个 需要更好地理解介导这种并发症的机制， 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 通路，介导SUD和情绪相关障碍。在人类中，L型钙通道（LTCC） 基因已被确定为可卡因依赖、重度抑郁症和 焦虑加剧在啮齿类动物模型中，我们已经发现，L-型钙通道（LTCC）的激活， 腹侧被盖区（VTA）增强可卡因相关的、抑郁样、焦虑样和快感缺失行为， 同时也导致社会赤字。我们还发现，LTCC阻断导致药物寻求减少， 行为通过调节多巴胺信号在脑桥核（NAc）。然而，该领域仍然缺乏 深入了解神经精神疾病中的LTCC机制。更具体地说， 对LTCC介导抑郁和焦虑相关表型的机制了解有限， 暴露于滥用药物或长期压力-代表着科学知识的空白。我们的初步 研究结果表明，可卡因戒断或慢性应激暴露大鼠的LTCC阻断诱导 抗焦虑样和抗抑郁样作用。在目前的提案中，我们将整合静脉注射药物自我- 行为药理学和体内给药和慢性不可预测应激（CUS）范式 在雄性和雌性大鼠中进行电化学（伏安法），以：1）确定LTCC阻断是否产生 抗焦虑样和抗抑郁样作用，并促进可卡因戒断期间的社会互动，通过 2）确定LTCC阻断是否减弱了DA信号传导的致焦虑性， 快感缺乏的影响，和社会互动赤字，CUS。在本提案中，我们将确定 LTCC阻断可作为缓解情绪障碍的新型治疗干预的机制 与反复接触可卡因或压力有关的症状。