Alcoholism is a major public health problem in the U.S.. Research into its interaction with the brain is far from conclusive. We propose to investigate the effects of ethanol on the locus coeruleus and on one of its major target areas, the hippocampus, because this system has been implicated in other types of addiction (opiates) and may have a major role in determining mood and modulating anxiety. Experiments will be conducted on tissue slices in vitro. Ethanol and other drugs will be introduced into the superfusing medium in known quantities. Iontophoretic and intracellular injection of drugs will also be done when indicated. Neurons will be impaled with glass micro-electrodes, and the membrane voltage amplified and measured, using standard electrophysiological techniques. Membrane resistance will be measured with a bridge arrangement and the cells will at times be voltage clamped using a one-electrode voltage clamp device. The slice will be stimulated directly to elicit synaptic potentials. We will be examining three major research questions: l) The effects of ethanol on the membrane properties and synaptic input characteristics of the neurons. These will include the membrane potential, membrane resistance, spike amplitude and threshold, the response to stimulation of synaptic inputs and the effects of bath applied transmitter substances; 2) The effects of ethanol on the calcium dependent potassium current, which is a major determinant of neuronal excitability. We will attempt to elucidate how ethanol interacts with intracellular calcium and cyclic nucleotides to affect this current; 3) The effects of ethanol will be compared with a number of membrane fluidizing agents to test the hypothesis that membrane fluidization is the molecular mechanism of action of ethanol.