The neuropeptide galanin coexists with acetylcholine in the septohippocampal pathway, relevant to learning, memory, and Alzheimer's disease. Galanin fibers and terminals are overexpressed in the cholinergic basal forebrain in Alzheimer's disease. John Robinson completed an in vivo microdialysis study showing that administration of galanin into the region of the cholinergic cell bodies, the medial septum/diagonal band of Broca, inhbits release of acetylcholine in the terminal field, the ventral hippocampus. This year, Mike McDonald worked out conditions for lesioning cholinergic neurons in the basal forebrain of the rat with the cholinergically selective immunotoxin, 192IgG- saporin. This lesion produced a loss of cholinergic markers and deficits in the delayed non-matching to position memory task which were analogous to those seen in Alzheimer's dementia. Galanin produced a further deficit in performance on the memory task, in rats with cholinergic deficits analogous to moderate stages of Alzheimer's disease. These findings indicate that galanin overexpression may contribute to the dementia symptoms, and that galanin receptor antagonists may be a useful adjunct therapy to existing cholinergic therapies for treating Alzheimer's dementia. The neuropeptide cholecystokinin coexists with dopamine in the mesolimbic pathway projecting to the shell of the nucleus accumbens. A selective cholecystokinin receptor antagonist, L-365,260, increased amphetamine- induced behaviors, specifically in rats that were characterized as low sucrose consumers. The paradigm, designed by Dr. Sills, detects individual differences in propensity for rewarded behaviors. This year, Dr. Sills employed in vivo microdialysis to measure dopamine release from the nucleus accumbens of HIGH versus LOW rats. HIGH sucrose consumers showed larger increases in dopamine release after amphetamine treatment, indicating that the mechanism underlying individual differences in responses to dopaminergic and cholecystokinin drugs on rewarded behaviors may be through a receptor mediating dopamine release, on the presynaptic dopaminergic terminals in the nucleus accumbens.
- National Institutes of Health: $825,232.00
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