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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054767-04
Application #
6181078
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1997-05-01
Project End
2001-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
4
Fiscal Year
2000
Total Cost
$244,729
Indirect Cost
Name
Stanford University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Bieda, Mark C; Su, Henry; Maciver, M Bruce (2009) Anesthetics discriminate between tonic and phasic gamma-aminobutyric acid receptors on hippocampal CA1 neurons. Anesth Analg 108:484-90
Sceniak, Michael P; Maciver, M Bruce (2008) Slow GABA(A) mediated synaptic transmission in rat visual cortex. BMC Neurosci 9:8
Winegar, Bruce D; MacIver, M Bruce (2006) Isoflurane depresses hippocampal CA1 glutamate nerve terminals without inhibiting fiber volleys. BMC Neurosci 7:5
Lukatch, Heath S; Kiddoo, Cynthia E; Maciver, M Bruce (2005) Anesthetic-induced burst suppression EEG activity requires glutamate-mediated excitatory synaptic transmission. Cereb Cortex 15:1322-31
Bieda, Mark C; MacIver, M Bruce (2004) Major role for tonic GABAA conductances in anesthetic suppression of intrinsic neuronal excitability. J Neurophysiol 92:1658-67
Gredell, J A; Turnquist, P A; Maciver, M B et al. (2004) Determination of diffusion and partition coefficients of propofol in rat brain tissue: implications for studies of drug action in vitro. Br J Anaesth 93:810-7
Pittson, Sky; Himmel, Allison M; MacIver, M Bruce (2004) Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices. BMC Neurosci 5:52
Lingamaneni, R; Krasowski, M D; Jenkins, A et al. (2001) Anesthetic properties of 4-iodopropofol: implications for mechanisms of anesthesia. Anesthesiology 94:1050-7
Nishikawa, K; MacIver, M B (2001) Agent-selective effects of volatile anesthetics on GABAA receptor-mediated synaptic inhibition in hippocampal interneurons. Anesthesiology 94:340-7
Nishikawa, K; MacIver, M B (2000) Excitatory synaptic transmission mediated by NMDA receptors is more sensitive to isoflurane than are non-NMDA receptor-mediated responses. Anesthesiology 92:228-36

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