Ethanol-Neurosteroid Actions on Synaptic Transmission

乙醇神经类固醇对突触传递的作用

• 批准号: 6917799
• 负责人: JILLA SABETI
• 金额: $ 4.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917799
• 关键词: NMDA receptors; alcoholism /alcohol abuse; biological models; drug interactions; electrophysiology; enzyme activity; ethanol; hippocampus; laboratory rat; long term potentiation; membrane potentials; memory; neural information processing; neural transmission; neuropharmacology; neurotoxicology; pharmacokinetics; phosphotransferases; postdoctoral investigator; pregnenolone; sectioning; steroids; synapses; tissue /cell preparation; western blottings

DESCRIPTION (provided by applicant): Chronic ethanol produces many neurological disorders, including memory and cognitive impairments. Alterations in hippocampal synaptic transmission may underlie the effects of ethanol on learning and memory. It has been suggested that the effects of ethanol on CNS function may be mediated by neurosteroids, which are synthesized de novo in brain. Both ethanol and neurosteroids influence excitatory and inhibitorysynaptic transmission by interacting with N-methyl-d-aspartate (NMDA)- and gamma-aminobutyric acid receptors. However, it is not clear how chronic ethanol alters the modulatory effects of neurosteroids on hippocampal synaptic function that is important for memory processing. The proposal will focus on pregnenolone sulfate (PREGS), a potent memory-enhancing neurosteroid, and its interaction with ethanol on NMDA receptor-mediated synaptic transmission and potentiation. The hypothesis being tested is that NMDA receptor-mediated synaptic responses to PREGS are altered by chronic intermittent ethanol (CIE) treatment. Field excitatory post synaptic potentials will be measured from CA1 neurons in hippocampal slices prepared from ethanol-nai've and CIE treated rats. The effect of CIE treatment on PREGSinduced changes in NMDA-receptor mediated synaptic transmission and long-term potentiation will be investigated. Furthermore, the persistence of these alterations will be examined in neuronal slices from rats withdrawn from CIE treatment. Finally, it will be determined whether alterations in kinase activity are involved in the interactions of ethanol and PREGS on long-term potentiation. Collectively, the experiments will advance our understanding of changes in neurosteroid modulation of synaptic function that may be important to the CNS actions of ethanol.

描述（由申请人提供）：慢性乙醇会产生许多神经系统疾病，包括记忆和认知障碍。海马突触传递的改变可能是乙醇影响学习记忆的基础。研究表明，乙醇对中枢神经系统功能的影响可能是由脑内从头合成的神经甾体介导的。乙醇和神经甾体均通过与N-甲基-D-天冬氨酸（NMDA）和γ-氨基丁酸受体相互作用影响兴奋性和突触传递。然而，目前尚不清楚慢性乙醇如何改变神经甾体对海马突触功能的调节作用，这对记忆加工很重要。该提案将集中于硫酸双烯醇酮（PREGS），一种有效的增强记忆的神经类固醇，及其与乙醇对NMDA受体介导的突触传递和增强的相互作用。正在测试的假设是，NMDA受体介导的突触反应PREGS改变慢性间歇性乙醇（CIE）治疗。场兴奋性突触后电位将从由乙醇未处理和CIE处理的大鼠制备的海马切片中的CA 1神经元测量。将研究CIE处理对PREGS诱导的NMDA受体介导的突触传递和长时程增强的变化的影响。此外，将在退出CIE治疗的大鼠的神经元切片中检查这些变化的持续性。最后，它将确定是否在激酶活性的改变参与乙醇和PREGS的相互作用对长时程增强。总的来说，这些实验将促进我们对神经类固醇调节突触功能的变化的理解，这可能对乙醇的CNS作用很重要。