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Cognitive Performances of Cholinergically Depleted Rats Following Chronic Donepezil Administration

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Cognitive Performances of Cholinergically Depleted Rats Following Chronic Donepezil Administration
  JournalofAlzheimer'sDisease17(2009) 161-176001 10.3233/JAD-2009-1040IOSPress Cognitive Performances of CholinergicallyDepleted Rats Following Chronic DonepezilAdministration Debora Cutulia,c, Francesca Fotia,c, Laura Mandolesia,b, Paola De Bartoloa,c, Francesca Gelfoa,b,Francesca Federicoa,d and Laura Petrosinia,c,* aIRCCS Santa Lucia Foundation, Rome, ItalybUniversity o/Naples "Parthenope H,  Naples, Italy c  Department o/ Psychology, University o/ Rome "La Sapienza  H,  Rome, ItalydUniversity o/Siena, Siena, Italy Communicated by Sigfrido Scarpa 161 Abstract. Since acute and chronic administration of the acetylcholinesterase inhibitors, namely donepezil, improves cognitivefunctions in patients affiicted by mild to moderate dementia and reverses memory deficits in experimental models of leamingand memory, it seemed interesting to assess the effects of chronic donepezil treatment on cognitive functions in adult rats withforebrain cholinergic depletion. Lesions were performed by means of intracerebroventricular injections of the immunotoxin 192IgG-saporin. The cognitive functions oflesioned animals treated or not treated with donepezil were compared with those of intactanimals. Cholinergic depletion affected working memory functions, weakened procedural competencies, affected the acquisitionoflocalizing knowledge, and evoked remarkable compulsive and perseverative behaviors. In lesioned animals, chronic donepeziltreatment ameliorated localizatory capabilities, performances linked to cognitive f1exibility and procedural abilities. Furthermore,it attenuated compulsive deficits. The present data indicate positive effects of chronic donepezil treatment on specific cognitive performances, suggesting that an aimed use of acetylcholinesterase inhibitors, targeting some symptoms more than others, may be beneficiai in the case of cholinergic hypofunction. The animai model used in the present research may provide an efficientmethod for analyzing cognition-enhancing drugs before clinical trials.Keywords: Acetylcholinesterase inhibitor, behavioral testing, cholinergic neurotransmission, cognitive f1exibility, forebraincholinergic system, 192 IgG-saporin, mnesic functions INTRODUCTION Mode1s of memory hypothesize that leaming is as-sociated with increased acetylcholine (ACh) transmis-sion  [1-3).  Clinical studi es report that disruption of cholinergic transmission results in impaired memoryand attention functions in normal aging as well as in pathological conditions, such as mild cognitive impair- •Corresponding author: Prof. Laura Petrosini, Department ofPsy-chology, University ofRome "La Sapienza", Via dei Marsi 78,00185Rome, ltaly. Tel.lFax: +390649917522; E-mail: laura.petrosini@uniroma1. it. ment (MCI) [4,5] and Alzheimer's disease (AD) [6,7).As the progressive loss of cholinergic neurons in theneocortex and in the hippocampus [8] and the resultingreduction in ACh levels correlate with the degree of cognitive decline in AD ("cholinergic hypothesis" of AD)  [9-14],  pharmacological treatments directed to-ward the cholinergic system have been suggested as potentially useful in AD [4,15). To date, pharmaco-logical treatment of mild to moderate AD continuesto target the cholinergic system, reporting some suc-cess in maintaining and/or enhancing cognitive func-tioning  [16-18). ISSN 1387-2877/09/$17.00  @  2009 - IOS Press and the authors. Ali rights reserved 
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