ANESTHETIC ACTIONS AT GABA AND GLUTAMATE SYNAPSES

描述：(改编自申请人的摘要)证据存在于 中枢神经系统(CNS)突触的麻醉作用。一些人 麻醉药可能增强GABA介导的抑制性传递，而其他药物 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。 这些调查人员的初步结果表明，有几个 麻醉药作用于这两种类型的突触，并可能相加以减少 突触诱发的神经元放电。调查员建议说 有可能开发选择性靶向麻醉剂，基于 了解谷氨酸和GABA突触的作用。要做到这一点，请 不同脑区共同突触动作的测定 提出了麻醉药的化学/药理分类。具体的 目的是确定：1)麻醉剂引起的抑郁的程度 CA1神经元的放电是由增强的GABA介导的传递引起的。 2)麻醉是否引起谷氨酸介导的突触抑制 反应包括增强的GABA抑制。3)细胞和分子 谷氨酸和GABA突触的麻醉作用机制。这个 拟议的研究将使用大鼠特征良好的CA 1神经元电路 海马区，其中GABA和谷氨酸介导快速单突触 变速箱。诱发反应将被选择性GABA完全阻断 和谷氨酸受体拮抗剂。电生理记录将是 联合选择性NMDA和AMPA受体拮抗剂研究 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 麻醉诱导的CA1神经元放电抑制可被以下药物逆转 阻断GABA受体/氯离子通道。

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.