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

• 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
• 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

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一个主要障碍是戒断期间药物复发率高。暴露于药物相关的线索，诱导可卡因渴望和可卡因寻求行为，可以加速可卡因复发。然而，到目前为止，还没有FDA批准的药物治疗可卡因成瘾。因此，我们必须了解可卡因寻求行为的神经生物学机制，以便能够确定新的治疗靶点，以防止这种复发性疾病。药物相关的线索引起腹侧被盖区（VTA）多巴胺（DA）神经元的爆发性放电，导致中脑核（NAc）中的阶段性DA释放。从我们的实验室的工作表明，阶段性DA活动在腹侧被盖区的NAc电路，和腹侧被盖区胆碱能受体调节这种活动，是关键的线索诱导的可卡因寻求。然而，在可卡因戒断过程中介导阶段性多巴胺释放和线索诱导的药物寻求行为的确切机制仍然知之甚少。我们以前已经表明，Cav1.3 L型Ca2+通道（LTCCs）和其下游的Ca2+激活通路在腹侧被盖区DA神经元是至关重要的敏感的心理行为反应，可卡因后，长期戒断。此外，我们最近的研究结果表明，Cav1.3通道促进DA神经元从紧张性放电到爆发性放电的转变，并通过胆碱能机制起作用，这强烈表明Cav1.3通道的募集可能是线索诱导的可卡因寻找行为的基础。因此，本R21应用的目标是检验以下假设：VTA Cav1.3机制通过调节NAc中的阶段性DA释放来构成线索诱导的可卡因寻求行为的基础。为了实现这一目标，我们将使用一种创新和综合的实验方法，使用药理学和病毒载体介导的基因敲除在VTA中结合行为测试和体内伏安法在NAc中，检查线索诱导的可卡因寻求在戒断过程中，使用临床前自我给药大鼠模型。在具体目标1中，我们将研究VTA Cav1.3通道在早期和长期戒断期间线索诱导的可卡因寻找中的作用。在具体目标2中，我们将在体内研究VTA Cav1.3通道在早期和长期戒断过程中VTA诱发和乙酰胆碱受体介导的NAc阶段性DA释放中的作用。从这项研究中获得的机制见解将提供对药物复吸的神经生物学的新理解，并将确定Cav1.3通道是否可以作为预防可卡因复吸的潜在新治疗靶点。