Pre-clinical evaluation of effects of acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: PET study in conscious monkeys

Abstract

The present review described the effects of acetylcholinesterase (AChE) inhibition on the cerebral cholinergic neuronal system in the conscious monkey brains with PET. Somatosensory stimulation induced a regional cerebral blood flow (rCBF) response, revealed with [(15)O]H(2)O, in the contralateral somatosensory cortex. Scopolamine resulted in an abolished rCBF response to stimulation, and this abolished rCBF response was recovered by physostigmine, donepezil, and tacrine. Donepezil suppressed AChE activity, analyzed by [(11)C]MP4A, in all cortical regions in a dose-dependent manner. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex as measured by microdialysis. Binding of [(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 by donepezil. These results demonstrated that PET imaging with specifically labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful tool for pre-clinical evaluation of novel drugs.