Ethanol-Neurosteroid Actions on Synaptic Transmission

乙醇神经类固醇对突触传递的作用

• 批准号: 6793054
• 负责人: JILLA SABETI
• 金额: $ 4.3万
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793054
• 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 Furthermore, the persistence of these alterations will be examined in neuronal slices from rats withdrawn from CIE treatment.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）：慢性乙醇会导致许多神经系统疾病，包括记忆和认知障碍。海马突触传递的改变可能是乙醇对学习和记忆的影响的基础。有人认为，乙醇对中枢神经系统功能的影响可能是由神经类固醇介导的，神经类固醇是在大脑中从头合成的。乙醇和神经类固醇都通过与 N-甲基-d-天冬氨酸 (NMDA) 和 γ-氨基丁酸受体相互作用来影响兴奋性和抑制性突触传递。然而，目前尚不清楚长期乙醇如何改变神经类固醇对海马突触功能的调节作用，而海马突触功能对记忆处理很重要。该提案将重点关注孕烯醇酮硫酸盐 (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，慢性间歇性乙醇 (CIE) 治疗会改变 NMDA 受体介导的突触对 PREGS 的反应。场兴奋性突触后电位将从未经乙醇处理和 CIE 处理的大鼠海马切片中的 CA1 神经元测量。将研究 CIE 治疗对 PREGS 诱导的 NMDA 受体介导的突触传递和长期增强变化的影响。此外，这些改变的持续性将在从 CIE 治疗中退出的大鼠的神经元切片中进行检查。最后，将确定激酶活性的改变是否与乙醇和 PREGS 的长期增强相互作用有关。总的来说，这些实验将增进我们对神经类固醇调节突触功能的变化的理解，这可能对乙醇的中枢神经系统作用很重要。