The long-term goal of this work is to develop a pharmacological treatment regimen for the cognitive dysfunctions involving cholinergic neurons associated with aging and Alzheimer's disease. Specifically, this project will investigate the cholinergic mechanisms involved in regulating cholinergic neurons projecting to the cortex and hippocampus. Multiple types of cholinergic receptors with differing regional distributions have been identified in the central nervous system. It is postulated that stimulation of cholinergic receptors in the region of cell bodies of basal forebrain cholinergic neurons is inhibitory to these neurons. Furthermore, these receptors may differ significantly from postsynaptic cholinergic receptors so that cholinergic neurotransmission can be effectively enhanced by cholinergic antagonists which block presynaptic receptors but not postsynaptic receptors. The cholinergic receptors involved in this mechanism will be characterized in an animal model which allows the study of the effect of selected agonists and antagonists on the activity of cholinergic neurons and on behavior in an intact, fully functional animal. The effect of cholinergic drugs injected into the nucleus basalis or the medial septum through chronically-implanted guide cannulas will be studied on cholinergic activity in the frontal cortex, parietal cortex and hippocampus and on memory in conscious rats. Central cholinergic activity will be assessed by quantitating acetylcholine (ACh) turnover by a mass fragmentographic technique that measures the relative incorporation of deuterium label from phosphorylcholine into choline and ACh. The 8-arm radial maze will be used to test memory and obtain a functional correlate of ACh turnover. The effect of intra-basal forebrain (nucleus basalis or medial septum) injection of carbachol, nicotine, and oxotremorine-M will be studied on ACh turnover and short-term, or working, memory. Furthermore, depending upon the results of the agonist studies, the ability of some or all of the following antagonists to block the action of carbachol, will be studied: mecamylamine, atropine, pirenzepine, AF-DX 116 and hexahydrosila-difenidol.
