Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning

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 re lease as well as acting as an acetylcholinesterase (AChE) inhibitor. Gal wa s tested in two preclinical experiments. In Experiment 1 with 16 young and 16 older rabbits, Gal (3.0 mg/kg) was administered for 15 days during condi tioning, and the drug significantly improved learning, reduced AChE levels, and increased nicotinic receptor binding. In Experiment 2, 53 retired bree der rabbits were tested over a 15-wk period in four conditions. Groups of r abbits received 0.0 (vehicle), 1.0, or 3.0 mg/kg Gal for the entire 15-wk p eriod or 3.0 mg/kg Gal for 15 days and vehicle for the remainder of the exp eriment. Fifteen daily conditioning sessions and subsequent retention and r elearning assessments were spaced at 1-month intervals. The dose of 3.0 mg/ kg Gal ameliorated learning deficits significantly during acquisition and r etention in the group receiving 3.0 mg/kg Gal continuously. Nicotinic recep tor binding was significantly increased in rabbits treated for 15 days with 3.0 mg/kg Gal, and all Gal-treated rabbits had lower levels of brain AChE, The efficacy of Gal in a learning paradigm severely impaired in AD is cons istent with outcomes in clinical studies.