Effects of S-8510, a novel benzodiazepine receptor partial inverse agonist, on basal forebrain lesioning-induced dysfunction in rats.
We investigated the effects of a novel benzodiazepine partial inverse agonist, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine monophosphate monohydrate), on the impairment of spatial memory, decreased high-affinity choline uptake and acetylcholine release in basal forebrain-lesioned rats. S-8510 (3 and 5 mg/kg, p.o. 30 min before each training session) significantly ameliorated the basal forebrain-lesion-induced impairment of spatial memory in water maze task. In vivo brain microdialysis studies showed that systemic administration of S-8510 at 3 and 10 mg/kg significantly increased the release of acetylcholine in the front-parietal cortex in basal forebrain-lesioned rats. Further, repeated administration of S-8510 (3 and 10 mg kg(-1) day(-1) for 5 days) reversed the decrease in cortical high-affinity choline uptake induced by basal forebrain lesion. Thus, S-8510 improved the spatial memory impairment induced by lesion of the basal forebrain in rats. In addition, it increased acetylcholine release and high-affinity choline uptake from the cortex, a region closely associated with memory, in basal forebrain-lesioned rats. These results indicate that S-8510 has cognition enhancing and cholinergic-activating effects in the basal forebrain-lesioned rats, suggesting that this agent may be useful for the treatment of mild to moderate senile dementia including Alzheimer's disease.
Abe
K
K
Department of Pharmacology, Development Research Laboratories, Shionogi, Toyonaka, Osaka, Japan. kohji.abe@shionogi.co.jp
Takeyama
C
C
Yoshimura
K
K
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002794:Choline / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D058785:GABA-A Receptor Agonists; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism
D058785:GABA-A Receptor Agonists; D018697:Nootropic Agents; D011963:Receptors, GABA-A; C105893:S 8510; D001569:Benzodiazepines; D002795:Choline O-Acetyltransferase; D002794:Choline; D000109:Acetylcholine