Chronic nicotine infusion in rats has been found in our studies with the radial-arm maze to improve working memory function. This type of chronic nicotine infusion models that achieved by the nicotine skin patch, an increasingly common way to administer nicotine which has been found in our studies to effectively improve cognitive function in schizophrenics, Alzheimer's disease patients and adults with attention deficit disorder. The proposed studies will help determine the critical neural systems underlying chronic nicotine infusion-induced memory improvement. The primary hypothesis is that nicotinic receptors in the hippocampus are critical for the nicotine infusion effect on memory. We have found that ibotenic acid lesions of neurons in the ventral hippocampus eliminates the effectiveness of chronic nicotine for improving memory. Also we have found that local ventral hippocampal infusion of the nicotinic antagonists mecamylamine, DH-beta-E and MLA cause significant deficits in working memory. MLA effectively blocks alpha-7 receptors, DH-beta-E effectively blocks alpha-3 beta-4 receptors and mecamylamine effectively blocks alpha-3 beta-4 receptors all of which are found in the hippocampus. These three nicotinic antagonists will be infused either during the development of the chronic nicotine effect or during its expression to determine the involvement of these nicotinic receptors in different phases of the chronic nicotine effect on memory. In the later phases of the project similar studies will be carried out in other brain areas including the dorsal hippocampus, medial and lateral frontal cortex, nucleus accumbens and the midbrain dopaminergic nuclei. This will further complete our analysis of the neural bases for chronic nicotine effects on memory. These studies will further our understanding of the neural systems underlying cognitive function and dysfunction. This will be of critical importance for the development of nicotinic-based therapeutics for cognitive dysfunction.
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