The overall goal of this study is to identify cellular and membrane events responsible for anesthesia, the seizure activity characteristics of high pressure nervous syndrome (HPNS), and pressure-anesthetic antagonism. There are three major hypotheses to be tested. 1. Anesthesia is a unitary single-site phenomenon: All agents induce a common essential change in membrane properties. Alternatively, anesthesia can be brought about by different molecular changes specific to each class of agent. 2. Pressure """"""""reversal"""""""" of anesthesia represents a direct opposing effect of anesthetics and pressure at the same molecular site in nerve membrane. Alternatively, pressure antagonism is indirect. 3. HPNS seizures are due to mechanisms of neuronal synchronization similar to those implicated in more common seizure models. Studies will be carried out in isolated vertebrate brain preparations (turtle visual cortex, rat hippocampal cortex) using intracellular recording. Determinants of cellular excitability to be included in tests of the hypotheses are resting and action potential properties, including those of calcium-dependent action potentials; after-potentials due to calcium-dependent potassium channels; excitatory and inhibitory synaptic transmission; and synaptic facilitation. Collaborative work is planned with other laboratories (1) to test the relevance of the findings to anesthesia and HPNS in animals and (2) to explore in detail the effects of pressure on inhibitory synapses. Toward the end of the project period, it is planned to begin to characterize at the molecular level changes in individual ion channel properties identified as relevant in the intracellular studies, using techniques of patch clamp recording from single ion channels.
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