Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning.

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Woodruff-Pak DS, Vogel RW 3rd, Wenk GL

Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning.

Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2089-94. Epub 2001 Feb 6.

PubMed ID

11172080 [ View in PubMed

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Abstract

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. Gal was 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 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 Gal for the entire 15-wk period or 3.0 mg/kg Gal 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 Gal ameliorated learning deficits significantly during acquisition and retention in the group receiving 3.0 mg/kg Gal continuously. Nicotinic receptor 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 consistent with outcomes in clinical studies.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Galantamine	Acetylcholinesterase	Protein	Humans	Yes	Inhibitor	Details
Galantamine	Neuronal acetylcholine receptor subunit alpha-7	Protein	Humans	Yes	Allosteric modulator	Details