Roles for Gliotransmission in Substance Abuse

描述(由申请人提供)：突触的可塑性至少是滥用药物成瘾的细胞基础之一。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发挥着关键作用。注射可卡因可导致腹侧被盖区(VTA)NMDA受体依赖性突触传递的长时程增强。VTA内注入NMDA受体拮抗剂可阻止可卡因诱导的条件性位置偏爱。我们将测试这一新的假设，即星形胶质细胞对控制NMDA受体功能、突触可塑性以及由此导致的成瘾行为至关重要。对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的钙信号刺激这些神经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，从而产生了三方突触的想法，这解释了星形胶质细胞在突触传递中的作用。利用胶质细胞传递受损的可诱导的、星形胶质细胞特异的转基因小鼠系，我们获得了对该项目至关重要的两个观察结果：第一，抑制神经胶质传递显著降低突触NMDA受体密度。其次，这种对神经胶质传递的抑制减弱了可卡因诱导的条件性位置偏爱。鉴于NMDA受体在调节滥用药物的奖赏特性方面的已知重要性，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，从而调节对滥用药物的行为反应。具体目的I：验证胶质传递调节VTA内多巴胺能神经元功能性NMDA受体密度的假说。具体目的II：检验胶质传递促进VTA突触可塑性的假说。具体目标III：检验神经胶质传递对可卡因诱导的行为反应至关重要的假设。系统地评估神经胶质传递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。由于星形胶质细胞表达独特的受体，可以作为治疗的靶点，该项目的成功可能为预防和治疗成瘾提供一种新的方法。公共卫生相关性：这项工作的目标是评估一种新的想法，即大脑中一种名为星形胶质细胞的非神经细胞在调节药物滥用的长期反应中发挥关键作用。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，并有可能为治疗的发展找到新的靶点。

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.