Roles for Gliotransmission in Substance Abuse

描述（由申请人提供）：突触可塑性至少是药物成瘾或滥用的细胞基础之一。NMDA受体是某些形式的突触可塑性所必需的，在介导对可卡因的行为反应中起着关键作用。可卡因输注可导致NMDA受体依赖性的腹侧被盖区（VTA）突触传递的长期增强。NMDA受体拮抗剂输注到VTA防止可卡因诱导的条件位置偏好。我们将验证星形胶质细胞对NMDA受体功能、突触可塑性以及成瘾行为的控制至关重要的新假设。星形胶质细胞在控制突触传递中的作用有了新的认识。1994年，我们发现星形胶质细胞Ca2+信号刺激这些胶质细胞释放化学递质。从那时起，我们和其他人已经证明，这种胶质传递过程可以调节神经元的兴奋性和突触传递，从而导致了三方突触的想法，这说明了星形胶质细胞在突触传递中的作用。使用可诱导的星形胶质细胞特异性转基因小鼠系，我们对该项目进行了两个重要的观察：首先，抑制胶质传递显著降低突触NMDA受体密度。其次，这种对胶质传递的抑制减弱了可卡因诱导的条件位置偏好。鉴于NMDA受体在介导药物滥用的奖励特性中的已知重要性，我们假设星形胶质细胞调节神经元NMDA受体密度和突触可塑性，从而调节对药物滥用的行为反应。具体目的一：验证胶质传递调节VTA多巴胺能神经元功能性NMDA受体密度的假设。具体目的二：验证胶质传递促进VTA突触可塑性的假设。具体目的三：验证神经胶质传递对可卡因诱导的行为反应至关重要的假设。系统地评估胶质传递在突触可塑性和滥用药物的行为反应中的作用，有望为成瘾的细胞机制提供新的见解。由于星形胶质细胞表达独特的受体，可以靶向治疗，这个项目的成功可能提供一种预防和治疗成瘾的新方法。公共卫生相关性：这项工作的目的是评估一种新的想法，即大脑中被称为星形胶质细胞的非神经元细胞在介导对药物滥用的长期反应中起关键作用。系统地评估星形胶质细胞在突触可塑性和药物滥用行为反应中的作用，有望为成瘾的细胞机制提供新的见解，并有可能为治疗方法的发展确定新的靶点。

DESCRIPTION (provided by applicant): Synaptic plasticity is at least one of the cellular underpinnings of addiction to drugs of abuse. NMDA receptors, which are necessary for some forms of synaptic plasticity, play pivotal roles in mediating behavioral responses to cocaine. Infusion of cocaine can lead to NMDA receptor-dependent long term potentiation of synaptic transmission in the ventral tegmental area (VTA). Infusion of NMDA receptor antagonists into the VTA prevent cocaine-induced conditioned place preference. We will test the novel hypothesis that astrocytes are critical for the control of NMDA receptor function, synaptic plasticity, and as a consequence addictive behaviors. There is a new appreciation for roles of astrocytes in the control of synaptic transmission. In 1994 we discovered that astrocytic Ca2+ signals stimulate the release chemical transmitters from these glia. Since then we and others have shown that this process of gliotransmission can regulate neuronal excitability and synaptic transmission leading to the idea of the Tripartite Synapse, which accounts for roles of astrocytes in synaptic transmission. Using lines of inducible, astrocyte-specific transgenic mice impaired in gliotransmission we have made two observations essential for this project: First, inhibiting gliotransmission significantly reduces synaptic NMDA receptor density. Second, this inhibition of gliotransmission blunts cocaine-induced conditioned place preference. Given the known importance of NMDA receptors in mediating rewarding properties of drugs of abuse we hypothesize that astrocytes regulate neuronal NMDA receptor density and synaptic plasticity and thereby behavioral responses to drugs of abuse. Specific Aim I: Test the hypothesis that gliotransmission regulates functional NMDA receptor density on dopaminergic neurons in the VTA. Specific Aim II: Test the hypothesis that gliotransmission promotes synaptic plasticity in the VTA. Specific Aim III: Test the hypothesis that gliotransmission is essential for cocaine-induced behavioral response. Systematically evaluating the role of gliotransmission in synaptic plasticity and behavioral responses to drugs of abuse promises to offer new insights into the cellular mechanisms underlying addiction. Since astrocytes express unique receptors that could be targeted therapeutically, success in this project may offer a new approach to prevent and treat addictions. PUBLIC HEALTH RELEVANCE: The goal of this work is to evaluate the novel idea that a non-neuronal cell of the brain called the astrocyte plays a pivotal role in mediating the long-term response to drugs of abuse. Systematically evaluating the role of astrocytes in synaptic plasticity and behavioral responses to drugs of abuse promises to offer new insights into the cellular mechanisms underlying addiction and the potential to identify new targets for the development of therapeutics.