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NEUROPHARMACOLOGY

Comparison of Galantamine and Donepezil for Effects on Nerve Growth Factor, Cholinergic Markers, and Memory Performance in Aged Rats

Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, Georgia (C.M.H., D.A.G., E.J.H., L.W.D., M.L.M., S.P.W., A.V.T.); Small Animal Behavior Core, Medical College of Georgia, Augusta, Georgia (A.V.T.); Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia (A.V.T.); Department of Psychology, University of Michigan, Ann Arbor, Michigan (V.P.); and Department of Biostatistics, Medical College of Georgia Augusta, Georgia (J.L.W.)

This study was designed to determine 1) whether repeated exposures to the acetylcholinesterase inhibitors (AChEIs) galantamine (GAL) or donepezil (DON) resulted in positive effects on nerve growth factor (NGF) and its receptors, cholinergic proteins, and cognitive function in the aged rat, and 2) whether GAL had any advantages over DON given its allosteric potentiating ligand (APL) activity at nicotinic acetylcholine receptors. Behavioral tests (i.e., water maze and light/dark box) were conducted in aged Fisher 344 rats during 15 days of repeated (subcutaneous) exposure to either GAL (3.0 or 6.0 mg/kg/day) or DON (0.375 or 0.75 mg/kg/day). Forty-eight hours after the last drug injection, cholinergic receptors were measured by [¹²⁵I]-(±)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([¹²⁵I]IPH; epibatidine analog), ¹²⁵I--bungarotoxin (¹²⁵I-BTX), [³H]pirenzepine ([³H]PRZ), and [³H]-5,11-dihydro-11-[((2-(2-((dipropylamino)methyl)-1-piperidinyl)ethyl)amino)carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one methanesulfonate ([³H]AFDX-384, or [³H]AFX) autoradiography. Immunochemical methods were used to measure NGF, high (TrkA and phospho-TrkA)- and low (p75 neurotrophin receptor)-affinity NGF receptors, choline acetyltransferase (ChAT), and the vesicular acetylcholine transporter (VAChT) in memory-related brain regions. Depending on dose, both GAL and DON enhanced spatial learning (without affecting anxiety levels) and increased [¹²⁵I]IPH, [³H]PRZ, and [³H]AFX (but decreased ¹²⁵I-BTX) binding in some cortical and hippocampal brain regions. Neither AChEI was associated with marked changes in NGF, NGF receptors, or VAChT, although DON did moderately increase ChAT in the basal forebrain and hippocampus. The results suggest that repeated exposures to either GAL or DON results in positive (and sustained) behavioral and cholinergic effects in the aged mammalian brain but that the APL activity of GAL may not afford any advantage over acetylcholinesterase inhibition alone.

Address correspondence to Dr. Alvin V. Terry, Jr., Professor, UGA College of Pharmacy, Director, Small Animal Behavior Core, CJ-1020, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA 30912-2450. E-mail: aterry{at}mail.mcg.edu