Nefiracetam ameliorates associative learning impairment in the scopolamine-injected older rabbit.
BACKGROUND
The cognition-enhancing drug, nefiracetam, is in Phase III clinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisition of delay eyeblink classical conditioning in older rabbits, a form of associative learning with striking behavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioning engages 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.


METHODS
To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiological and behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the 750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamine to 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 with 1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioning stimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam.


RESULTS
Rabbits injected with 1.5 mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly the behavioral impairment.


CONCLUSIONS
Nefiracetam had ameliorating effects on a task impaired in AD in an animal model of AD: older rabbits with cholinergic system antagonism.
Pak
Jonathan
J
Cognitive Neuroscience Laboratory, Albert Einstein Healthcare Network, Philadelphia, PA 19141, USA.
Green
John
J
Heifets
Boris
B
Pak
Michelle
M
Woodruff-Pak
Diana
D
D000375:Aging / Q000523:psychology*; D000818:Animals; D001245:Association Learning / Q000187:drug effects*; D018680:Cholinergic Antagonists / Q000633:toxicity; D003215:Conditioning, Eyelid / Q000187:drug effects*; D005260:Female; D006624:Hippocampus / Q000503:physiopathology; D007859:Learning Disabilities / Q000139:chemically induced / Q000517:prevention & control*; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D011930:Reaction Time / Q000187:drug effects; D012601:Scopolamine / Q000633:toxicity; D012688:Septum Pellucidum / Q000503:physiopathology; D013047:Specific Pathogen-Free Organisms; D013268:Stimulation, Chemical
D018680:Cholinergic Antagonists; D018697:Nootropic Agents; D011760:Pyrrolidinones; C058876:nefiracetam; D012601:Scopolamine