Role of Endocannabinoid Signaling in Alcoholism

内源性大麻素信号传导在酒精中毒中的作用

• 批准号: 6776009
• 负责人: Basavaraj S Balapal
• 金额: $ 9.99万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776009
• 关键词: alcoholism /alcohol abuse; amidohydrolases; anandamide; cannabinoid receptor; cannabinoids; cell surface receptors; chronic disease /disorder; electrophysiology; evoked potentials; fatty acids; gamma aminobutyrate; genetically modified animals; glutamate receptor; laboratory mouse; laboratory rat; neural transmission; neurophysiology; neurotoxicology; newborn animals; single cell analysis; tissue /cell culture

DESCRIPTION (provided by applicant): Alcohol (EtOH) suppress the excitatory neurotransmission and potentiate the inhibitory neurotransmission whereas AEA released by postsynaptic neurons is shown to inhibit neurotransmitter release by activating CB1 receptors (CB1 R) at presynaptic neurons. The purpose of this project is to gain a better understanding of anandamide (AEA) and CB1Rs role in the action of EtOH on neurotransmission at synapses between granular neurons, interneuron, Purkinje cells. In our approach we use cerebellar mixed neurons in culture. This preparation offers the unique possibility that granular cells and interneurons establish synaptic contacts with Purkinje cells as they do in the intact cerebellum and are known to use glutamate or GABA as a neurotransmitter. Our researches will focus on the role of AEA and CB1Rs in the action of EtOH on the spontaneous and evoked excitatory and inhibitory synaptic transmission. Additional experiments will also test whether or not novel AEA receptors are involved in the action of EtOH on the spontaneous and evoked synaptic transmission using cells from CB1R knockout mice pups. In the first specific aim, we will test whether or not AEA and CB1Rs are involved in the action of EtOH on the spontaneous and evoked excitatory and inhibitory synaptic transmission. We will measure the EPSC and IPSC amplitude and mEPSC and mlPSC frequency and amplitude in acute EtOH exposed cells in the presence or absence of receptor modulators. In specific aim 2, we will measure the chronic EtOH-induced changes in CB1R and FAAH immunoreactivity and the role of AEA and CB1Rs in the effects of chronic EtOH on IPSC and EPSC amplitudes and mlPSC and mEPSC frequency and amplitude. In aim 3, we will study how the lack of CB1Rs influences the effects of acute and chronic EtOH on IPSC and EPSC amplitudes and mlPSC and mEPSC frequency and amplitude. The better understanding of these mechanisms will yield new drug therapies with potential in treatment of alcoholism.

描述（由申请人提供）： 酒精 (EtOH) 抑制兴奋性神经传递并增强抑制性神经传递，而突触后神经元释放的 AEA 通过激活突触前神经元的 CB1 受体 (CB1 R) 来抑制神经递质释放。该项目的目的是更好地了解 anandamide (AEA) 和 CB1Rs 在 EtOH 对颗粒神经元、中间神经元、浦肯野细胞之间突触神经传递的作用中的作用。在我们的方法中，我们在培养物中使用小脑混合神经元。这种制备提供了独特的可能性，即颗粒细胞和中间神经元与浦肯野细胞建立突触接触，就像它们在完整小脑中所做的那样，并且已知使用谷氨酸或 GABA 作为神经递质。我们的研究将集中于 AEA 和 CB1R 在 EtOH 对自发和诱发的兴奋性和抑制性突触传递的作用中的作用。其他实验还将使用来自 CB1R 敲除小鼠幼崽的细胞来测试新型 AEA 受体是否参与 EtOH 对自发和诱发突触传递的作用。在第一个具体目标中，我们将测试 AEA 和 CB1R 是否参与 EtOH 对自发和诱发的兴奋性和抑制性突触传递的作用。我们将在存在或不存在受体调节剂的情况下测量急性 EtOH 暴露细胞中的 EPSC 和 IPSC 幅度以及 mEPSC 和 mlPSC 频率和幅度。在具体目标 2 中，我们将测量慢性 EtOH 诱导的 CB1R 和 FAAH 免疫反应性变化，以及 AEA 和 CB1R 在慢性 EtOH 对 IPSC 和 EPSC 幅度以及 mlPSC 和 mEPSC 频率和幅度的影响中的作用。在目标 3 中，我们将研究 CB1R 的缺乏如何影响急性和慢性 EtOH 对 IPSC 和 EPSC 振幅以及 mlPSC 和 mEPSC 频率和振幅的影响。对这些机制的更好理解将产生具有治疗酒精中毒潜力的新药物疗法。