Cocaine-induced neuroplasticity: a new role for TGF beta signaling

可卡因诱导的神经可塑性：TGFβ信号传导的新作用

基本信息

批准号：
8853842
负责人：
DAVID M DIETZ
金额：
$ 38.54万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8853842
关键词：
Actins Activin Receptor Activins Address Animals Behavior Behavioral Brain Cell Nucleus Chronic Cocaine Cocaine Abuse Cocaine Dependence Complex Cues Data Dendritic Spines Development Disease Dopamine Drug Addiction Event Gene Targeting Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Health Human Lead Left Light MADH3 gene Maintenance Maps Measures Mediating Mission Molecular Morphology Neuronal Plasticity Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Pharmacotherapy Proteins Psychostimulant dependence Public Health Receptor Activation Receptor Signaling Regulation Relapse Reporting Research Rewards Rodent Role Self Administration Self-Administered Signal Pathway Signal Transduction Stream Structure Testing Therapeutic Agents Time Transcriptional Regulation Transforming Growth Factor beta Withdrawal Work addiction base cocaine exposure combat craving drug craving drug of abuse drug seeking behavior effective therapy extracellular member neuroadaptation neuromechanism novel overexpression psychostimulant receptor expression relating to nervous system research study success transcription factor

项目摘要

DESCRIPTION (provided by applicant): The proposed studies investigate the role of activin receptor signaling cascades in mediating the long-lasting changes in the brain's reward circuits, which contribute to the complex behavioral abnormalities that comprise an addicted state. To date there is no effective pharmacotherapy for addiction to stimulants, such as cocaine, highlighting the dire need for further understanding of how such drugs of abuse "re-wire" the brain. Neuronal plasticity is considered a neural substrate of the long-term addicted state, but there is a scarcity of mechanistic evidence that explores the molecular mechanism of cocaine-induced structural plasticity. Guided by exciting preliminary data demonstrating that in the Nucleus Accumbens (NAc) of animals of self-administering cocaine, activin receptor expression and signaling is increased, this application will test the following hypotheses: (Aim I) cocaine self-administration regulates the activin receptor-Smad pathway. Consequently, following cocaine self-administration the activin-smad pathway regulates both (a) actin dynamics and (b) Smad gene targets; (Aim II) Activin-Smad pathways are key molecular mechanisms underlying cocaine-induced dendritic spine plasticity of NAc neurons following cocaine self-administration; (Aim III) Activin receptor and Smad signaling pathways directly mediate cocaine seeking and craving as measured by reinstatement behaviors. This application presents an opportunity to determine, for the first time, the causal role for TGFBeta/activin-smad signaling cascades in facilitating drug seeking behaviors by examining cocaine-induced plasticity on cellular (i.e. structural) and behavioral levels (i.e. reinstatement). The findings from the work in this application will elucidate mechanisms by which chronic cocaine exposure induces long-term changes in plasticity of NAc neurons, and provides new directions for the development of novel therapies for cocaine addiction.

描述（由申请人提供）：拟议的研究研究了激活素受体信号级联反应在介导大脑奖励电路的持久变化中的作用，这有助于构成上瘾状态的复杂行为异常。迄今为止，还没有有效的药物治疗可卡因等刺激剂的成瘾药物，强调了迫切需要进一步了解这种滥用药物如何“重新分割”大脑。神经元可塑性被认为是长期上瘾状态的神经底物，但是有大量的机械证据探讨了可卡因诱导的结构可塑性的分子机制。在令人兴奋的初步数据的指导下，表明在自我管理可卡因的动物核（NAC）中，激活素受体表达和信号传导增加了，该应用将测试以下假设：（目标I）可卡因自我管理可以调节激活素受体受体受体。 - 史密斯途径。因此，随着可卡因自我给药，激活素-SMAD途径调节（a）肌动蛋白动力学和（b）SMAD基因靶标。（AIM II）激活素-SMAD途径是可卡因自我给药后NAC神经元的可卡因诱导的树突状脊柱可塑性的关键分子机制；（AIM III）激活素受体和SMAD信号通路直接介导可卡因寻求和渴望，如恢复行为所测量。该应用为首次确定TGFBETA/AIVIVIN-SMAD信号级联的因果作用提供了一个机会，通过检查可卡因诱导的细胞（即结构）和行为水平（即恢复原状），通过检查可卡因诱导的可塑性来促进药物寻求行为。该应用程序中的发现将阐明慢性可卡因暴露会导致NAC神经元可塑性的长期变化，并为开发可卡因成瘾的新疗法提供新的方向。