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C. A. MURPHY, W. ARIAS, A. CHEN, W. ALOSIO, D. HE, D. FEVERSTON, L. SANCHEZ, M. NELSON, S. BENT, R. MUSHLIN, J. WATSON-JOHNSON, L. MENALLED, S. RAMBOZ, E. SCHAEFFER, M. BECONI, L. PARK

Acetylcholinesterase inhibitors have been demonstrated to improve learning and memory in a number of animal models of cognitive dysfunction, as well as being a standard of treatment in patients exhibiting clinical signs of memory loss. Donepezil (Aricept) is a centrally acting reversible acetylcholinesterase inhibitor which has been extensively studied for its efficacy on measures of cognitive processing and attention. The progressive neurodegenerative disorder Huntington’s disease (HD), which is caused by a polyglutamine repeat expansion within the huntingtin protein, is characterized by movement disorders, cognitive impairment and psychiatric symptoms. The 120 repeat R6/2 mouse model of HD expresses a human transgene containing exon 1 of the mutant huntingtin gene and faithfully replicates many of the symptoms of the disease, including progressive loss of body weight, marked impairments in cognition, and severe motor deficits. This study tested for a positive effect of donepezil (0.3 and 0.6 mg/kg, IP, 1 hour pretreatment time, start of dosing 1 week prior to swim test) on the performance of R6/2 mice in a simple visual discrimination task, the two-choice swim test. In this test, mice are individually placed in the center of a water-filled tank – one side of the tank has a cue light directly above the water and an escape platform just under the water’s surface and the other side of the tank is dark and does not have an escape platform. Mice quickly learn to swim to the light-cued side, and upon reaching a predefined acquisition criterion, a reversal phase is conducted in which mice now must learn that the platform is located on the dark side of the tank. At 9 weeks of age, R6/2 mice typically exhibit a modest deficit in acquisition of this task, and a more severe deficit in reversal learning. In our first study, we observed a significant improvement in both the acquisition and reversal phases of the task in mice treated with 0.6 mg/kg donepezil. A follow-up study replicated the positive effect of donepezil on reversal learning in a second group of mice. Neither dose of donepezil significantly affected open field locomotion, rearing behavior, or body weight of the R6/2 mice. We can conclude that cognitive impairment characteristic of the R6/2 transgenic model of HD shares neurochemical similarities with many other types of dementia.