ly-404187 and Alcoholic-Intoxication

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.

Topics: Alcoholic Intoxication; Analysis of Variance; Animals; Behavior, Animal; Biphenyl Compounds; Brain; Brain Mapping; Central Nervous System Depressants; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Excitatory Amino Acid Agonists; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Motor Activity; Oxygen; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Sulfonamides; Time Factors