ULTRA-LOW EXPOSURE TO ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR PARTIAL AGONISTS ELICITS AN IMPROVEMENT IN COGNITION THAT CORRESPONDS WITH AN INCREASE IN ALPHA-7 RECEPTOR EXPRESSION IN RODENTS: IMPLICATIONS FOR LOW DOSE CLINICAL EFFICACY

摘要

Alpha-7 neuronal nicotinic receptors (NNRs) are considered targets for cognitive enhancement in schizophrenia and Alzheimer's disease. AZD0328 is an alpha-7 NNR partial agonist that enhances cognition in rodents and non-human primates at sub-microgram to microgram doses. We hypothesized that increased expression of the alpha-7 receptor contributes to this beneficial activity at low doses and tested this by examining the effect of AZD0328 using in vivo and ex vivo binding, RT-PCR and cognitive function in rodents. AZD0328 (0.00178 mg/kg) was subcutaneously administered to mice 4, 24, 48 and 72 hours prior to testing in novel object recognition and produced a significant increase in cognition at 4, 24 and 48 h post-dosing. In vivo binding was examined in rat brain using [~3H]AZ11637326 and there was a dose-dependent reduction in receptor binding at higher doses of AZD0328 (0.001-3 mg/kg), and a second alpha-7 partial agonist, SSR180711 (0.01-30 mg/kg). Lower doses of both compounds (0.0001 mg/kg) produced a significant increase in binding of [~3H]AZ11637326. Ex vivo binding using [~(125)l]-alpha-bungarotoxin, showed a significant increase in receptor number (B_(max)) in the frontal cortex or hippocampus with no significant effect on receptor affinity (K_d) 2 h post administration of AZD0328. [~3H]AZ11637326 administered 1.5 h following AZD0328 produced a significant increase in specific binding in rat brain regions. We found that the effect on receptor number was long-lasting, with [~(125)l]-alpha-bungarotoxin binding increased in rats given AZD0328 for 2-48 h, but this was not accompanied by increased mRNA synthesis. SSR180711 produced a similar increase in B_(max) and specific binding with no effect on K_d. Therefore, trace dose of alpha-7 partial agonists has rapid onset and produces a profound, sustained effect on novel object recognition in mice that corresponds by dose to an increase in receptor number in rat brain. These findings provide an explanation for t...