ANESTHETIC ACTIONS AT GABA AND GLUTAMATE SYNAPSES

GABA 和谷氨酸突触的麻醉作用

• 批准号: 2701782
• 负责人: M. Bruce MacIver
• 金额: $ 21.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2701782
• 关键词: AMPA receptors; NMDA receptors; anesthetics; central nervous system; chloride channels; electrophysiology; evoked potentials; gamma aminobutyrate; glutamates; halothane; hippocampus; inhalation anesthesia; inhibitor /antagonist; ionophores; isoflurane; laboratory rat; neurons; neuropharmacology; receptor expression; synapses; thiopental

DESCRIPTION: (Adapted from the applicant's abstract) Evidence exists for anesthetic actions at central nervous system (CNS) synapses. Some anesthetics may enhance GABA-mediated inhibitory transmission while others appear to produce CNS depression by reducing glutamate-mediated excitation. Preliminary results from these investigators suggests that several anesthetics act at both types of synapses and may summate to reduce synaptically-evoked discharge of neurons. The investigator suggests that it may be possible to develop selectively targeted anesthetics based on an understanding of actions at glutamate and GABA synapses. To do this a determination of common synaptic actions of different chemical/pharmacological classes of anesthetics is proposed. The Specific Aims are to determine: 1) the extent to which anesthetic-induced depression of CA 1 neuron discharge results from enhanced GABA-mediated transmission. 2) whether anesthetic-induced depression of glutamate-mediated synaptic responses involves enhanced GABA inhibition. 3) the cellular and molecular mechanisms of anesthetic effects at glutamate and GABA synapses. The proposed research will use the well-characterized CA 1 neuron circuit in rat hippocampus, in which GABA and glutamate mediate fast monosynaptic transmission. Evoked responses will be completely blocked by selective GABA and glutamate receptor antagonists. Electrophysiological recordings will be combined with selective NMDA and AMPA receptor anatagonists to investigate anesthetic-induced depression of glutamate-mediated excitatory postsynaptic potentials. Parallel studies will determine the extent to which an anesthetic-induced depression of CA 1 neuron discharge can be reversed by blocking GABA receptor/Cl- channels.

描述：（改编自申请人的摘要）有证据表明 对中枢神经系统（CNS）突触的麻醉作用。 一些 麻醉剂可能会增强 GABA 介导的抑制性传播，而其他药物可能会增强 GABA 介导的抑制性传播 似乎通过减少谷氨酸介导的兴奋而产生中枢神经系统抑制。 这些研究人员的初步结果表明，一些 麻醉剂作用于两种类型的突触，并且可能相加以减少 神经元突触诱发放电。 调查人员建议， 或许可以根据以下情况开发选择性靶向麻醉剂： 了解谷氨酸和 GABA 突触的作用。 要做到这一点 确定不同的共同突触动作 提出了麻醉剂的化学/药理学类别。 具体 目的是确定：1​​) 麻醉引起的抑郁程度 CA 1 神经元放电是 GABA 介导的传递增强的结果。 2）麻醉是否会引起谷氨酸介导的突触抑制 反应涉及增强的 GABA 抑制。 3）细胞和分子 谷氨酸和 GABA 突触的麻醉作用机制。 这 拟议的研究将使用大鼠体内已充分表征的 CA 1 神经元回路 海马体，其中 GABA 和谷氨酸介导快速单突触 传播。 诱发反应将被选择性 GABA 完全阻断 和谷氨酸受体拮抗剂。 电生理记录将 结合选择性 NMDA 和 AMPA 受体拮抗剂进行研究 麻醉诱导的谷氨酸介导的兴奋性突触后抑制 潜力。 平行研究将确定在多大程度上 麻醉引起的 CA 1 神经元放电抑制可以通过以下方法逆转： 阻断 GABA 受体/Cl- 通道。