BACKGROUND: The cognition-enhancing drug, nefiracetam, is in Phase IIIclinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisitionof delay eyeblink classical conditioning in older rabbits, a form of associative learning with strikingbehavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioningengages the septo-hippocampal cholinergic system and is disrupted when the cholinergic system is antagonized.Delay eyeblink classical conditioning is impaired in normal aging and severely disrupted in AD. MATERIAL/METHODS:To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiologicaland behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamineto simulate disruption of the cholinergic system in AD. Three doses of nefiracetam (5, 10, or 15 mg/kg)were also injected in older rabbits receiving 1.5 mg/kg scopolamine. Control groups were treated with1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioningstimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam. RESULTS: Rabbits injected with 1.5mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly thebehavioral impairment. CONCLUSIONS: Nefiracetam had ameliorating effects on a task impaired in AD inan animal model of AD: older rabbits with cholinergic system antagonism.

Keywords: Aging, Association Learning, Cholinergic Antagonists, Conditioning, Eyelid, Hippocampus, Learning Disorders, Nootropic Agents, Pyrrolidinones, Reaction Time, Research Support, Non-U.S. Gov, Scopolamine, Septum Pellucidum, Specific Pathogen-Free Organisms, Stimulation, Chemical