The acetylcholinesterase inhibitor, ENA 713 (Exelon), attenuates the working memory impairment induced by scopolamine in an operant DNMTP task in rats

Rationale: The disruption of working memory in the delayed non-matching to position (DNMTP) task by the muscarinic antagonist, scopolamine, is conside red to be a model of the spatial working memory deficit in Alzheimer's dise ase (AD) patients. Objective: To investigate whether ENA 713 (Exelon) (0.1, 0.5 mg/kg, IP), an acetylcholinesterase inhibitor. would reverse the effec ts 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 v ariations 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 confoun d the conclusions of the effect of drugs on working memory. Results: It was found that: (i) scopolamine significantly reduced choice accuracy delay-de pendently in both test situations while modifying non-mnemonic measures of task performance delay-independently, indicating an impairment of working m emory, (ii) ENA 713 (0.5 mg/kg) significantly attenuated the scopolamine-in duced impairment of working memory and significantly reduced the scopolamin e-induced changes in some non-mnemonic measures of task performance; (iii) the presence of barriers did not alter the effects of scopolamine and ENA 7 13 on working memory. Conclusion: ENA 713 reversed the working memory defic it induced by scopolamine. These results are consistent with the attenuatio n 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.