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.