ANESTHETIC ACTIONS AT GABA AND GLUTAMATE SYNAPSES

描述：（改编自申请人的摘要）存在以下证据： 中枢神经系统（CNS）突触的麻醉作用。 一些 麻醉剂可以增强GABA介导的抑制性传递，而其他麻醉剂可以增强GABA介导的抑制性传递， 似乎通过减少谷氨酸介导的兴奋而产生CNS抑制。 这些调查人员的初步结果表明， 麻醉剂作用于两种类型的突触， 神经元的突触诱发放电。 研究人员认为， 有可能开发出选择性靶向麻醉剂， 了解谷氨酸和GABA突触的作用。 为此， 确定不同神经元的共同突触作用 提出了麻醉剂的化学/药理学类别。 具体 目的是确定：1）麻醉诱导抑郁的程度 CA 1神经元放电的增强是GABA介导的传递的结果。 2)是否麻醉诱导的谷氨酸介导的突触抑制 反应涉及增强的GABA抑制。 3)的细胞和分子 谷氨酸和GABA突触的麻醉作用机制。 的 拟议的研究将使用大鼠中表征良好的CA 1神经元电路 海马，其中GABA和谷氨酸介导快速单突触 传输 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 联合选择性NMDA和AMPA受体拮抗剂， 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 麻醉诱导的CA 1神经元放电抑制可通过 阻断GABA受体/Cl-通道。

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.