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

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 [H-3]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 [H-3]AZ11637326. Ex vivo binding using [I-125]-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. [H-3]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 [129]-a-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 Kd. 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 the acute and sustained benefit of alpha-7 receptor activation in working memory in nonhuman primates and guidance for drug development initiatives and treatment regimens for nicotinic partial agonists. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.