Previous work showed that ethanol and other intoxicant-anesthetics increase resting intracellular calcium concentrations in neuronal and non-neuronal tissues. This effect may be responsible for ethanol/anesthetic-induced increases in mechanisms dependent on intracellular calcium including resting neurotransmitter release and calcium-dependent potassium conductances. In this proposal. it is hypothesized that ethanol increases resting intracellular calcium concentrations by releasing calcium from a non-mitochondrial intracellular storage site. This calcium store may also be released by other anesthetic agents but is distinguishable from the calcium store released by inositol trisphosphate a second messenger generated in many different tissues following receptor-mediated stimulation. In the proposed studies, the relationship between the intracellular calcium stores released by ethanol and other anesthetics and the calcium stores released by inositol trisphosphate will be defined in tissues from brain and liver and in PC12 cells. Potential mechanisms of ethanol/anesthetic-induced calcium release from intracellular stores will also be distinguished. The role of ethanol-induced calcium release from this intracellular calcium store in tolerance and dependence development will be evaluated. Possible endogenous regulators of this ethanol-sensitive calcium store will also be investigated. The presence of an ethanol/anesthetic-releasable calcium store in brain and liver indicates that findings from the proposed studies may have bearing on possible pharmacological treatments for ethanol abuse and addiction and acute toxic effects of ethanol and other anesthetics.
