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Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: Functional imaging of the conscious monkey brain using animal PET in combination with microdialysis
Author(s) -
Tsukada Hideo,
Nishiyama Shingo,
Fukumoto Dai,
Ohba Hiroyuki,
Sato Kengo,
Kakiuchi Takeharu
Publication year - 2004
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.10310
Subject(s) - microdialysis , neuroscience , cholinergic , acetylcholinesterase , cholinergic system , pet imaging , brain function , cholinergic neuron , medicine , pharmacology , positron emission tomography , biology , central nervous system , biochemistry , enzyme
This study demonstrated the effects of acute acetylcholinesterase (AChE) inhibition by donepezil (Aricept) on the cerebral cholinergic neuronal system in the brains of young (5.2 ± 1.1 years old) and aged (20.3 ± 2.6 years old) monkeys ( Macaca mulatta ) in the conscious state. Donepezil at doses of 50 and 250 μg/kg suppressed AChE activity, analyzed by metabolic rate (k 3 ) of N ‐[ 11 C]methyl‐4‐piperidyl acetate ([ 11 C]MP4A), in all cortical regions in a dose‐dependent manner in both age groups. However, the suppression degree was more marked in young than in aged monkeys. AChE inhibition by donepezil resulted in a dose‐dependent increase in acetylcholine levels in the prefrontal cortex of young animals as measured by microdialysis. Binding of (+) N ‐[ 11 C]propyl‐3‐piperidyl benzilate ([ 11 C](+)3‐PPB) to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [ 11 C](+)3‐PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition. These results demonstrate that the PET imaging technique with specific labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful method to clarify the mechanism of drugs in the living brains of experimental animals. Synapse 52:1–10, 2004. © 2004 Wiley‐Liss, Inc.