Abstract
We present a substantial series of behavioral and imaging experiments, which demonstrate, for the first time, that increasing AMPA receptor-mediated neurotransmission via administration of potent and selective biarylsulfonamide AMPA potentiators LY404187 and LY451395 reverses the central effects of an acutely intoxicating dose of ethanol in the rat. Using pharmacological magnetic resonance imaging (phMRI), we observed that LY404187 attenuated ethanol-induced reductions in blood oxygenation level dependent (BOLD) in the anesthetized rat brain. A similar attenuation was apparent when measuring local cerebral glucose utilization (LCGU) via C14-2-deoxyglucose autoradiography in freely moving conscious rats. Both LY404187 and LY451395 significantly and dose-dependently reversed ethanol-induced deficits in both motor coordination and disruptions in an operant task where animals were trained to press a lever for food reward. Both prophylactic and acute intervention treatment with LY404187 reversed ethanol-induced deficits in motor coordination. Given that LY451395 and related AMPA receptor potentiators/ampakines are tolerated in both healthy volunteers and elderly patients, these data suggest that such compounds may form a potential management strategy for acute alcohol intoxication.
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Acknowledgements
This research was funded by Eli Lilly and Co. Ltd. The MRI spectrometer was provided by the University of London Intercollegiate Research Service scheme and is located at Queen Mary and Westfield College London managed by Dr Alasdair Preston.
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This research was funded by Eli Lilly and Co Ltd. Marcus Messenger, Michael O'Neill, Gary Gilmour, Rosa Simmons, Smirti Iyengar, and Mark Tricklebank are employed by Eli Lilly and Co Ltd. Vincenzo Libri was employed by Eli Lilly and Co Ltd when the experiments were conducted.
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Jones, N., Messenger, M., O'Neill, M. et al. AMPA Receptor Potentiation can Prevent Ethanol-Induced Intoxication. Neuropsychopharmacol 33, 1713–1723 (2008). https://doi.org/10.1038/sj.npp.1301562
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DOI: https://doi.org/10.1038/sj.npp.1301562
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