In schizophrenia, it has been hypothesized that sensory gating abnormalities may be an underlying inherited deficit in the individuals brain that alters its sensitivity to repeated stimuli, i.e., sensory gating. Patients with schizophrenia are often heavy smokers and it is currently believed that a short-lived beneficial therapeutic affect it achieved through smoking on brain sensory processing. Although this affect is involved with the nicotinic cholinergic effects of nicotine, the finding of rapid desensitization which occurs to nicotinergic receptors suggests that another more long-lived modulatory may be involved with the therapeutic effects of nicotine in these patients. The purpose of the application will be to investigate the hypotheses that nicotinergic activation of hippocampal circuitry will lead to changes in sensory gating that are mediated, in part, through increases in extracellular levels of nitric oxide in discrete anatomical regions of the hippocampus. These studies will be conducted using a recently developed microvoltammetric sensor that is very selective and sensitive for direct spatially and temporally resolved measures of NO changes in the extracellular space of the brain. These studies will investigate the effects of cholinergic agnonists and antagonists of NO release in the extracellular space of the rat hippocampus slices, anethesized rats and free-moving animals. In addition, the potential interrelationships between sensory gating and NO signaling will be investigated measuring evolved potentials and NO release in the same animal. The studies should contribute to a better understanding of AChergic mechanisms that may be involved in NO signaling in the rat hippocampus, and potential role(s) of NO in schizophrenia.
