Long-term treatment with GTS-21 or nicotine enhances water maze performance in aged rats without affecting the density of nicotinic receptor subtypes in neocortex

Abstract

The synthetic nicotinic agonist GTS-21 and nicotine were compared in aged rats for their ability to enhance cognition and affect the density of brain nicotine receptor subtypes. At 15 min before to daily behavioral testing in the Morris water maze, aged rats were injected intraperitoneally with GTS-21 (2.6 μmoles/kg; 1.0 mg/kg), nicotine (1.2 μmoles/kg; 0.2 mg/kg), or saline. After 1 month of treatment, the density of α7 and α4β2 nicotinic receptor subtypes in the brain was determined using [125I]α-bungarotoxin and [3H]cytisine binding assays, respectively. Compared to saline controls, GTS-21 and nicotine-treated rats showed significantly greater water maze acquisition, but not greater memory retention. GTS-21 treatment caused an increase in the density of α4β2 binding sites in the neostriatum, but not in the neocortex, and did not affect α7 binding site densities in any of the brain areas analyzed. Nicotine treatment had no effect on either α4β2 binding site densities in the brain areas evaluated. Because GTS-21 acts preferentially on brain nicotinic receptors while having little activity at neuromuscular junction nicotinic receptors, these results indicate that GTS-21 may have therapeutic value to treat age-associated memory impairment and/or Alzheimer's disease. Drug Dev. Res. 39:19–28. © 1997 Wiley-Liss, Inc.