Alzheimer's disease is associated with a significant reduction of cholinergic neurotransmission in the hippocampus. The application of exogenous cholinergic agonists and of acetylcholine esterase inhibitors has been shown to ameliorate some of the cognitive deficits associated with the disease thus it appears that enhancement of acetylcholine release in the hippocampus could be beneficial. Colocalization of galanin in the basal forebrain cholinergic neurons, projecting to the hippocampal formation of mammals, assumes a particular importance in this respect as it appears that galanin is also the most potent endogenous inhibitor of the evoked release of acetylcholine in the hippocampus. Observations on the galaninergic hyperinnervation of nucleus basalis in Alzheimer's disease also suggest that galanin may be of importance in the pathophysiology of the disease. The project aims at anatomical (light and electronmicroscopic), electrophysiological, biochemical and pharmacological study of the galanin- acetylcholine interactions in the septal-hippocampal formation in order to develop strategies for enhancement of cholinergic neurotransmission based on specific regulation of the galaninergic system. The hithertho neglected Galanin message associated peptide (GMAP) as well as galanin itself will be studied at the receptor- and second messenger levels with focus on their role as presynaptic regulators of ACh release. The role of galanin in sparing of cholinergic neurons and as a regulator (with NGF) of the survival of cholinergic basal forebrain neurons will be studied. The recently synthesized galanin receptor antagonist peptide : M15 (icv) has relieved the galanin mediated inhibition of hippocampal ACh release in vivo providing evidence for the usefulness of the development of galanin receptor antagonists for enhanced cholinergic transmission in the hippocampus and it also serves as the starting structure for the development of peptide-and peptidomimetic- galanin receptor antagonists. Design, synthesis, labeling, in vitro and in vivo tests of putative, M15 based galanin antagonists will be carried out in this project.
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