AMPA receptor potentiation can prevent ethanol-induced 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.
Jones
Nicholas
N
Neuroimaging Research Group, Institute of Psychiatry, Kings College London, London, UK. N.Jones@iop.kcl.ac.uk
Messenger
Marcus J
MJ
O'Neill
Michael J
MJ
Oldershaw
Anna
A
Gilmour
Gary
G
Simmons
Rosa M A
RM
Iyengar
Smriti
S
Libri
Vincenzo
V
Tricklebank
Mark
M
Williams
Steve C R
SC
D000435:Alcoholic Intoxication / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D001931:Brain Mapping; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000009:adverse effects*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D001713:Biphenyl Compounds; D002492:Central Nervous System Depressants; D018690:Excitatory Amino Acid Agonists; C430915:LY 404187; C512030:N-((2-(4'-(2-(methylsulfonyl)amino)ethyl)(1,1'-biphenyl)-4-yl)propyl)-2-propanesulfonamide; D018091:Receptors, AMPA; D013449:Sulfonamides; D000431:Ethanol; D010100:Oxygen