Nefiracetam ameliorates learning deficits in older rabbits and may act via the hippocampus

Behavioral and neurobiological parallels between rabbits and humans in eyeblink classical conditioning (EBCC) make this paradigm potentially useful for preclinical and clinical trials. The known involvement of hippocampal pyramidal cells in EBCC in rabbits led us to evaluate the nootropic compound, nefiracetam. In Expt. 1, 56 rabbits of a mean age of 27.9 months received daily doses of vehicle, 1, 3, 10, or 15 mg/kg nefiracetam 15 min before testing in the 750 ms delay EBCC paradigm. Trials to learning criterion (T/C) was significantly better with 10 mg/kg. To investigate whether nefiracetam ameliorated EBCC via the hippocampus, 20 older rabbits received bilateral hippocampal aspirations in Expt. 2. Eleven rabbits of a mean age of 26.8 months had histologically confirmed bilateral hippocampectomy and were dosed with vehicle or 10 mg/kg nefiracetam and tested with EBCC. Hippocampectomized rabbits treated with vehicle and 10 mg/kg nefiracetam had 718 and 996 T/C, respectively, that were not different from 845 T/C of 8 intact older rabbits and vehicle mg/kg nefiracetam, but significantly worse than 473 T/C for 8 intact older rabbits and 10 mg/kg nefiracetam. Nefiracetam ameliorated EBCC in older rabbits only when the hippocampus was intact.