Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning
Diana S. Woodruff-Pak, Richard W. Vogel III, and Gary L. Wenk
Research and Technology Development
Albert Einstein Healthcare Network, Philadelphia, PA 19141
Departments of Psychology and Diagnostic Imaging
Temple University, Philadelphia, PA 19122
Arizona Research Laboratories, Division of Neural Systems
Memory, and Aging, University of Arizona, Tucson, AZ 85724
Abstract
Classical eyeblink conditioning is a well-characterized model paradigm that engages the septohippocampal cholinergic system. This for Classical eyeblink conditioning is a well-characterized model paradigm that engages the septohippocampal cholinergic system. This form of associative learning is impaired in normal aging and severely disrupted in Alzheimer's disease (AD). Some nicotinic cholinergic receptor subtypes are lost in AD, making the use of nicotinic allosterically potentiating ligands a promising therapeutic strategy. The allosterically potentiating ligand galantamine (Gal) modulates nicotinic cholinergic receptors to increase acetylcholine release as well as acting as an acetylcholinesterase (AChE) inhibitor. galantamine was tested in two preclinical experiments. In Experiment 1 with 16 young and 16 older rabbits, galantamine (3.0 mg/kg) was administered for 15 days during conditioning, and the drug significantly improved learning, reduced AChE levels, and increased nicotinic receptor binding. In Experiment 2, 53 retired breeder rabbits were tested over a 15-wk period in four conditions. Groups of rabbits received 0.0 (vehicle), 1.0, or 3.0 mg/kg galantamine for the entire 15-wk period or 3.0 mg/kg galantamine for 15 days and vehicle for the remainder of the experiment. Fifteen daily conditioning sessions and subsequent retention and relearning assessments were spaced at 1-month intervals. The dose of 3.0 mg/kg galantamine ameliorated learning deficits significantly during acquisition and retention in the group receiving 3.0 mg/kg galantamine continuously. Nicotinic receptor binding was significantly increased in rabbits treated for 15 days with 3.0 mg/kg galantamine, and all galantamine-treated rabbits had lower levels of brain AChE. The efficacy of galantamine in a learning paradigm severely impaired in AD is consistent with outcomes in clinical studies.