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

The synthetic nicotinic agonist GTS-21 and nicotine were compared in a ged rats for their ability to enhance cognition and affect the density of brain nicotine receptor subtypes. At 15 min before to daily behavi oral testing in the Morris water maze, aged rats were injected intrape ritoneally with GTS-21 (2.6 mu moles/kg; 1.0 mg/kg), nicotine (1.2 mu moles/kg; 0.2 mg/kg), or saline. After 1 month of treatment, the densi ty of alpha 7 and alpha 4 beta 2 nicotinic receptor subtypes in the br ain was determined using [I-125] alpha-bungarotoxin and [H-3]cytisine binding assays, respectively. Compared to saline controls, GTS-21 and nicotine-treated rats showed significantly greater water maze acquisit ion, but not greater memory retention. GTS-21 treatment caused an incr ease in the density of alpha 4 beta 2 binding sites in the neostriatum , but not in the neocortex, and did not affect alpha 7 binding site de nsities in any of the brain areas analyzed. Nicotine treatment had no effect on either alpha 4 beta 2 binding site densities in the brain ar eas evaluated. Because GTS-21. acts preferentially on brain nicotinic receptors while having little activity at neuromuscular junction nicot inic receptors, these results indicate that GTS-21 may have therapeuti c value to treat age-associated memory impairment and/or Alzheimer's d isease. (C) 1997 Wiley-Liss, Inc.