In previous work I have demonstrated that brain essential fatty acid deficiency (EFAD) increases the sensitivity of rodents to a variety of volatile anesthetics and decreases their sensitivity to the volatile convulsant fluorothyl. Increased volatile anesthetic sensitivity was specifically reversed by a parenteral supplementation protocol (linoleic acid) that preferentially repleted the arachidonic acid content of cerebral cortical polyphosphoinositides. I propose to study the molecular mechanisms through which EFAD alters anesthetic/convulsant potency, and thus to gain insight into the molecular mechanisms of volatile anesthetic/convulsant action. To reach this goal, I propose three general areas of study: (1) To pursue my preliminary observations by studying the effects of brain EFAD and of volatile anesthetics/convulsants on the neurotransmitter-stimulated generation of phosphoinositide derived chemical second messengers (IP3, diacylglycerol, arachidonate metabolites). (2) To further characterize the model by determining the effects of EFAD on the potency of non-volatile anesthetics and convulsants and (3) To determine if EFAD alters the chemical interaction between anesthetics/convulsants and brain membranes using NMR spectroscopic techniques. The results of these three areas of investigation should provide new insights concerning the relationship(s) between whole animal anesthetic/convulsant effect, neuronal chemical composition and specific biochemical and/or physicochemical effects of anesthetics/convulsants.
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