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

描述（由申请人提供）：拟议的研究调查了激活素受体信号级联在介导大脑奖励回路中的长期变化中的作用，这有助于构成成瘾状态的复杂行为异常。迄今为止，尚无有效的药物治疗可卡因等兴奋剂成瘾，这突出表明迫切需要进一步了解这类滥用药物如何"重新连接"大脑。神经元可塑性被认为是长期成瘾状态的神经基质，但缺乏探索可卡因诱导的结构可塑性的分子机制的机制证据。在证明自我施用可卡因的动物的伏核（NAc）中，激活素受体表达和信号传导增加的令人兴奋的初步数据的指导下，本申请将测试以下假设：（目的I）可卡因自我施用调节激活素受体-Smad途径。因此，可卡因自我给药后，激活素-Smad通路调节（a）肌动蛋白动力学和（B）Smad基因靶标;（Aim II）激活素-Smad通路是可卡因自我给药后NAc神经元的可卡因诱导的树突棘可塑性的关键分子机制;（Aim III）激活素受体和Smad信号传导通路直接介导可卡因寻求和渴望，如通过恢复行为所测量的。本申请提供了一个机会，以确定，第一次，因果关系的作用，TGF β/激活素-smad信号级联在促进药物寻求行为通过检查可卡因诱导的可塑性细胞（即结构）和行为水平（即恢复）。本申请的研究结果将阐明慢性可卡因暴露诱导NAc神经元可塑性长期变化的机制，并为开发可卡因成瘾的新疗法提供新的方向。

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.