CaV 1.3 L-type Calcium Channel Mechanisms in Cocaine Seeking

CaV 1.3 可卡因寻找中的 L 型钙通道机制

基本信息

批准号：
8760356
负责人：
Nii A Addy
金额：
$ 26.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760356
关键词：
Agonist Behavior Behavioral Calcium Carbachol Cholinergic Receptors Cocaine Cocaine Dependence Cues Data Disease Dopamine Dose Exposure to FDA approved Foundations Future Genetic Goals Infusion procedures Investigation L-Type Calcium Channels Laboratories Mediating Modeling Molecular Molecular Target Muscarinic Acetylcholine Receptor Neurobiology Nicotinic Receptors Nifedipine Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Play Process Rattus Regulation Relapse Rewards Role Scanning Self Administration Sprague-Dawley Rats Sucrose Testing Tissues Ventral Tegmental Area Viral Vector Withdrawal Work addiction behavior test behavioral pharmacology cholinergic cocaine relapse prevention craving dopaminergic neuron drug craving drug relapse drug seeking behavior drug withdrawal genetic manipulation in vivo innovation insight male neurobiological mechanism new therapeutic target novel optogenetics pre-clinical prevent public health relevance research study response small hairpin RNA tool

项目摘要

DESCRIPTION (provided by applicant): A major barrier to successfully treating cocaine addiction is the high rate of drug relapse that occurs during periods of drug withdrawal. Cocaine relapse can be precipitated by exposure to drug-associated cues that induce cocaine craving and cocaine-seeking behavior. However, to date there are no FDA approved pharmacotherapies to treat cocaine addiction. Thus it is crucial that we understand the neurobiological mechanisms of cocaine-seeking behavior to be able to identify novel therapeutic targets to prevent this relapsing disorder. Drug-associated cues evoke burst firing of ventral tegmental area (VTA) dopamine (DA) neurons that results in phasic DA release in the nucleus accumbens (NAc). Work from our laboratory has revealed that phasic DA activity in the VTA to NAc circuit, and VTA cholinergic receptor regulation of such activity, is critical for cue-induced cocaine-seeking. However, the precise mechanisms that mediate phasic dopamine release and cue-induced drug-seeking behavior during cocaine withdrawal remain poorly understood. We have previously shown that Cav1.3 L-type Ca2+ channels (LTCCs) and their downstream Ca2+-activated pathways in VTA DA neurons are critical for sensitized psychomotor behavioral responses to cocaine following periods of prolonged withdrawal. Additionally our recent findings have revealed that Cav1.3 channels facilitate the transition of DA neurons from tonic to burst firing and act through cholinergic mechanisms, strongly suggesting that recruitment of Cav1.3 channels may underlie cue-induced cocaine-seeking behavior. Thus, the goal of this R21 application is to test the hypothesis that VTA Cav1.3 mechanisms underlie cue-induced cocaine-seeking behavior by regulating phasic DA release in the NAc. To achieve this goal, we will use an innovative and integrative experimental approach using pharmacology and viral vector-mediated genetic knockdown in the VTA in combination with behavioral testing and in vivo voltammetry in the NAc, to examine cue-induced cocaine seeking during withdrawal, using the preclinical self-administration rat model. In specific aim 1, we will examine the role of VTA Cav1.3 channels in cue-induced cocaine-seeking during early and protracted withdrawal. In specific aim 2, we will examine in vivo the role of VTA Cav1.3 channels in VTA-evoked- and acetylcholine receptor-mediated phasic DA release in the NAc during early and protracted withdrawal. The mechanistic insight gained from this study will provide new understanding of the neurobiology of drug relapse and will determine whether Cav1.3 channels may serve as a potential novel therapeutic target to prevent cocaine relapse.

描述（由申请人提供）：成功治疗可卡因成瘾的主要障碍是在戒毒期间发生的高药物复发率。可卡因复发可以通过暴露于诱导可卡因渴望和可卡因寻求可卡因的行为的药物相关线索来引起。但是，迄今为止，还没有FDA认可的药物治疗可卡因成瘾的药物疗法。因此，至关重要的是，我们了解寻求可卡因行为的神经生物学机制，能够鉴定出新的治疗靶标，以防止这种复发性疾病。与药物相关的提示引起了腹侧换段区域（VTA）多巴胺（DA）神经元的爆发，从而导致伏隔核（NAC）中的Phasic DA释放。我们实验室的工作表明，VTA到NAC电路中的阶段性DA活性，而这种活性的VTA胆碱能受体调节对于提示引起的可卡因寻求可卡因至关重要。但是，介导可卡因戒断期间阶段性多巴胺释放和提示诱导的药物寻求行为的确切机制仍然鲜为人知。我们先前已经表明，Cav1.3 L型Ca2+通道（LTCC）及其下游Ca2+激活的途径在VTA DA神经元中，对于延长戒断期后，对可卡因的敏化精神运动行为反应至关重要。此外，我们最近的发现表明，CAV1.3通道有助于通过胆碱能机制从滋补爆发到爆发和起作用，强烈表明CAV1.3通道可能是提示诱导的可卡因诱发的观察行为的基础。因此，该R21应用的目的是检验以下假设：VTA CAV1.3机制是通过调节NAC中的Phasic DA释放来构成提示引起的可卡因寻求行为的基础。为了实现这一目标，我们将使用药理学和病毒载体介导的VTA中的创新和综合实验方法与行为测试结合使用NAC中的行为测试和体内挥发性敲低，以使用临床前的自动加热率模型来检查提醒诱导的可卡因在戒断过程中寻求CUE诱导的可卡因模型。在特定的目标1中，我们将研究VTA CAV1.3通道在提早戒断和长期戒断过程中提示可卡因寻求可卡因的作用。在特定的目标2中，我们将在体内检查VTA CAV1.3通道在VTA诱发的 - 和乙酰胆碱受体介导的阶段性DA释放中在NAC中的早期和持久戒断中的作用。从这项研究中获得的机械洞察力将为药物复发的神经生物学提供新的了解，并将确定CAV1.3通道是否可以作为防止可卡因复发的潜在新型治疗靶标。