ANESTHETIC ACTIONS AT GABA AND GLUTAMATE SYNAPSES

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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.