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

基本信息

批准号：
10669182
负责人：
Nii A Addy
金额：
$ 37.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10669182
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 seeking 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

项目摘要

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（SUD）的人的情绪和动画障碍患病率更高，并且患有情绪障碍的人的SUD患病率也更高。戒毒时期也是与烦恼，焦虑症的增加和情绪障碍症状增加有关。更远，反复接触滥用药物或压力药物与情绪相关疾病有关。那，药物滥用和情绪障碍之间的合并症是该领域的持续挑战。有一个需要提高对介导这种合并症的机制的理解，以及对新颖和新颖的需求有效的治疗靶标。研究继续揭示重叠的机制，特别是在大脑奖励中途径，介导SUD和与情绪有关的疾病。在人类中，L型钙通道（LTCC）基因已被确定为可卡因依赖性，重度抑郁症和的候选风险基因动画增强。在啮齿动物模型中，我们发现L型钙通道（LTCC）的激活腹侧对盖区域（VTA）增强了与可卡因相关，类似抑郁症，焦虑和厌食的行为，同时还诱发了社会缺陷。我们还发现，LTCC封锁导致寻求毒品的拒绝通过调节伏隔核（NAC）中多巴胺信号传导的行为。但是，该领域仍然缺乏对神经精神疾病中LTCC机制的深度理解。更具体地说，有对LTCC机制的有限了解，导致抑郁症和动画相关的表型引起暴露于虐待或慢性压力的药物 - 代表科学知识的差距。我们的初步调查结果表明，可卡因戒酒或慢性应激暴露的大鼠的LTCC桶会影响抗焦虑样和抗抑郁药样作用。在当前的提案中，我们将整合静脉注射自我自我具有行为药理学和体内的给药和慢性不可预测的压力（CUS）范式雄性和雌性大鼠的电化学（伏安法）至：1）确定LTCC封锁是否产生类似抗焦虑药和抗抑郁药样效应，并通过可卡因禁欲期间促进社交互动调节DA信号传导和2）确定LTCC阻滞是否减弱了焦虑症和 Anhedonic效应，社会互动定义了CUS。在此提案中，我们将确定基础 LTCC封锁可以作为一种减轻情绪障碍的新型热干预的机制与重复接触可卡因或压力有关的症状。