Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography.
AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.
Division of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK. g.r.jordan@sms.ed.ac.uk
Graeme R
GR
Jordan
James
J
McCulloch
Mohammed
M
Shahid
David R
DR
Hill
Brian
B
Henry
Karen
K
Horsburgh
D000818:Animals; D001345:Autoradiography / Q000379:methods*; D001921:Brain / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002250:Carbon Radioisotopes / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003847:Deoxyglucose / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011810:Quinoxalines / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000819:agonists
D002250:Carbon Radioisotopes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003847:Deoxyglucose; D005947:Glucose