The acetylcholinesterase inhibitor, ENA 713 (Exelon), attenuates the working memory impairment induced by scopolamine in an operant DNMTP task in rats.
BACKGROUND
The disruption of working memory in the delayed non-matching to position (DNMTP) task by the muscarinic antagonist, scopolamine, is considered to be a model of the spatial working memory deficit in Alzheimer's disease (AD) patients.


OBJECTIVE
To investigate whether ENA 713 (Exelon) (0.1, 0.5 mg/kg, IP), an acetylcholinesterase inhibitor, would reverse the effects of scopolamine in the DNMTP task.


METHODS
Male Lister Hooded rats were trained to criterion in an operant DNMTP task (0- to 16-s delay intervals) before receiving vehicle, scopolamine (0.05 mg/kg, SC) alone, ENA 713 (0.1, 0.5 mg/kg, IP) alone, or combinations of scopolamine and ENA 713, in two variations of the task - with and without barriers inserted between the food magazine and the two levers. Barriers were inserted to prevent the use of positional strategies to perform the task, since this behaviour may confound the conclusions of the effect of drugs on working memory.


RESULTS
It was found that: (i) scopolamine significantly reduced choice accuracy delay-dependently in both test situations while modifying non-mnemonic measures of task performance delay-independently, indicating an impairment of working memory; (ii) ENA 713 (0.5 mg/kg) significantly attenuated the scopolamine-induced impairment of working memory and significantly reduced the scopolamine-induced changes in some non-mnemonic measures of task performance; (iii) the presence of barriers did not alter the effects of scopolamine and ENA 713 on working memory.


CONCLUSIONS
ENA 713 reversed the working memory deficit induced by scopolamine. These results are consistent with the attenuation of learning and memory disruptions due to cholinergic dysfunction by ENA 713 in other preclinical assays, and predict a drug-induced improvement in working memory in AD patients.
Ballard
T M
TM
Novartis Pharma Inc., Nervous System Department, WSJ-386.226, CH-4002 Basel, Switzerland,
McAllister
K H
KH
D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008568:Memory / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D048448:Phenylcarbamates; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D000068836:Rivastigmine; D012601:Scopolamine / Q000494:pharmacology*
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D012601:Scopolamine; D000068836:Rivastigmine