FACILITATION OF OLFACTORY LEARNING BY A MODULATOR OF AMPA RECEPTORS

The effects of a benzoyl-piperidine drug (BDP) that facilitates AMPA r eceptor-mediated synaptic responses were tested on the acquisition and retention of long-term memory at dosages that had no detectable effec ts on a variety of performance measures. BDP-12 produced a dose-depend ent suppression of exploratory activity in rats with statistically rel iable effects occurring at 50 mg/kg (i.p.). The drug had no effects on balance beam performance at 30 mg/kg but at 45 mg/kg reduced the numb er of crossings made within a session; it did not, however, affect the time required to perform a traversal. The performance of well-trained rats presented with a familiar pair of odors (correct and incorrect) was not detectably altered by BDP-12 at 30 mg/kg; however, the number of correct responses made in a five-trial test was reduced at 45 mg/kg . These results indicate that the AMPA receptor modulator at 30 mg/kg has little influence on arousal, motivation, sensori-motor processing, and attention; higher dosages cause a depression of learned and unlea rned prepotent responses. The effects of the lower concentration were tested on two-odor discrimination learning in rats that had extensive training on the task. The animals (n = 20) were given three or five ac quisition trials with novel odor pairs immediately after an injection of drug or vehicle and then tested 1-3 d later for retention in five u nrewarded probe trials. Retention performance was not significantly be tter than chance (52.6 +/- 4.5% correct) for odors learned on vehicle injection days but was well above chance for odors learned on drug inj ection days (70.6 +/- 4.2% correct). Within-subject comparisons confir med the memory enhancing effect of BDP-12 (p < 0.01). Analyses of perf ormance during five training trials indicated that the rats made more correct responses on days on which they were given the drug than on da ys on which they were injected with vehicle (p < 0.02). Within-subject differences in acquisition were correlated with differences in retent ion (r = 0.70). There were no evident effects of the drug on response latencies during acquisition. These results suggest that AMPA receptor modulators reduce the amount of training needed for the formation of long-term memory and do so at dosages which have little effect on vari ables that secondarily influence acquisition. Possible reasons for thi s selectivity are discussed.