title: Muscarinic receptor occupancy and cognitive impairment: a PET study with [11C](+)3-MPB and scopolamine in conscious monkeys.
abstract: The muscarinic cholinergic receptor (mAChR) antagonist scopolamine was used to induce transient cognitive impairment in monkeys trained in a delayed matching to sample task. The temporal relationship between the occupancy level of central mAChRs and cognitive impairment was determined. Three conscious monkeys (Macaca mulatta) were subjected to positron emission tomography (PET) scans with the mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre-, 2, 6, 24, and 48 h post-intramuscular administration of scopolamine in doses of 0.01 and 0.03 mg/kg. Occupancy levels of mAChR were maximal 2 h post-scopolamine in cortical regions innervated primarily by the basal forebrain, thalamus, and brainstem, showing that mAChR occupancy levels were 43-59 and 65-89% in doses of 0.01 and 0.03 mg/kg, respectively. In addition, dose-dependent impairment of working memory performance was measured 2 h after scopolamine. A positive correlation between the mAChR occupancy and cognitive impairment 2 and 6 h post-scopolamine was the greatest in the brainstem (P<0.00001). Although cognitive impairment was not observed 24 h post-scopolamine, sustained mAChR occupancy (11-24%) was found with both doses in the basal forebrain and thalamus, but not in the brainstem. These results indicate that a significant degree of mAChRs occupancy is needed to produce cognitive impairment by scopolamine. Furthermore, the importance of the brainstem cholinergic system in working memory in monkey is described.
authors: Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors: Shigeyuki
authors: S
authors: Yamamoto
authors: Shingo
authors: S
authors: Nishiyama
authors: Masahiro
authors: M
authors: Kawamata
authors: Hiroyuki
authors: H
authors: Ohba
authors: Tomoyasu
authors: T
authors: Wakuda
authors: Nori
authors: N
authors: Takei
authors: Hideo
authors: H
authors: Tsukada
authors: Edward F
authors: EF
authors: Domino
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D001931:Brain Mapping; D002247:Carbon Isotopes; D003072:Cognition Disorders / Q000139:chemically induced* / Q000000981:diagnostic imaging*; D003243:Consciousness; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008239:Lysine / Q000031:analogs & derivatives / Q000187:drug effects; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D008301:Maleimides; D018727:Muscarinic Antagonists / Q000633:toxicity*; D009483:Neuropsychological Tests; D010775:Photic Stimulation / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods; D011930:Reaction Time / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012601:Scopolamine / Q000633:toxicity*; D013997:Time Factors
chemical_list: D002247:Carbon Isotopes; D008301:Maleimides; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C047272:3-(N-maleimidopropionyl)biocytin; D012601:Scopolamine; D008239:Lysine