title: The AMPA receptor potentiator LY404187 increases cerebral glucose utilization and c-fos expression in the rat.
abstract: AMPA receptor potentiators enhance AMPA receptor-mediated glutamatergic neurotransmission and may have therapeutic potential as cognitive enhancers or antidepressants. The anatomical basis for the action of AMPA receptor potentiators is unknown. The aim of this study was to determine the effects of the biarylpropylsulfonamide AMPA receptor potentiator, LY404187 (0.05 to 5 mg/kg subcutaneously), upon cerebral glucose utilization and c-fos expression using 14C-2-deoxglucose autoradiography and c-fos immunocytochemistry. LY404187 (0.5 mg/kg) produced significant elevations in glucose utilization in 28 of the 52 anatomical regions analyzed, which included rostral neocortical areas and the hippocampus, as well the dorsal raphe nucleus, lateral habenula, and locus coeruleus. No significant decreases in glucose utilization were observed in any region after LY404187 administration. The increases in glucose utilization with LY404187 (0.5 mg/kg) were blocked by pretreatment with the AMPA receptor antagonist LY293558 (25 mg/kg), indicating that LY404187 acts through AMPA receptor-mediated mechanisms. LY404187 (0.5 mg/kg) also produced increases in c-fos immunoreactivity in the cortex, locus coeruleus, and the dorsal raphe nucleus. These studies demonstrate neuronal activation in key brain areas that are associated with memory processes and thus provide an anatomical basis for the cognitive enhancing effects of AMPA receptor potentiators.
authors.affiliation: Division of Clinical Neuroscience, University of Glasgow, Wellcome Surgical Institute, Garscube Estate, United Kingdom. Jill.Fowler@ed.ac.uk
authors.forename: Jill H
authors.initials: JH
authors.lastname: Fowler
authors.forename: Katherine
authors.initials: K
authors.lastname: Whalley
authors.forename: Tracey
authors.initials: T
authors.lastname: Murray
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'neill
authors.forename: James
authors.initials: J
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D003071:Cognition / Q000187:drug effects; D003847:Deoxyglucose; D005947:Glucose / Q000493:pharmacokinetics*; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D002250:Carbon Radioisotopes; C430915:LY 404187; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D013449:Sulfonamides; D003847:Deoxyglucose; D005947:Glucose