The effect of scopolamine in older rabbits tested in the 750 ms delay eyeblink classical conditioning procedure.

We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.

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. MATERIAL/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.