title: Effects of AMPA and clomethiazole on spreading depression cycles in the rat neocortex in vivo.
abstract: In hippocampal slices, inhibition of AMPA receptors unmasks synaptic transmission via NMDA receptors, suggesting that AMPA receptor activation normally inhibits synaptic transmission via NMDA receptors. Activation of NMDA receptors is involved in the pathogenesis of cortical spreading depression (CSD) which has been implicated in the pathogenesis of migraine aura and neuronal damage from peri-infarct depolarizations. In this study we examined whether NMDA receptor transmission could be unmasked in the neocortex in vivo by AMPA receptor blockage and whether AMPA receptors could affect CSD induced by 200 mM KCl. We further compared the effects of AMPA to those of the NMDA receptor antagonist, 2-amino-5-phosphono-pentanoic acid (2AP5), and the GABA-mimetic drug clomethiazole. The NMDA receptor antagonist MK-801 did not affect the baseline somatosensory evoked potentials (SEPs). In a medium with no Mg(2+), the AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) caused marked reduction in the SEP size which subsequently recovered partially; MK-801 blocked these partially recovered SEPs. AMPA (50 μM but not at 5 μM or 250 μM) and 2AP5 (10 μM) significantly reduced the number of CSD cycles. The effect of AMPA was not changed by co-applying it with cyclothiazide, which blocks AMPA receptor desensitization. Clomethiazole (100 mg/kg i.p.) did not significantly affect the number of CSD cycles. Only 2AP5 significantly reduced the potentiation that follows CSD. We conclude that activation of AMPA receptors can suppress the actions of NMDA receptors in the neocortex; this could be an intrinsic protective mechanism against CSD and also provide a possible therapeutic strategy against CSD-related neurological conditions.
authors.affiliation: Faculty of Medical Sciences, University of the West Indies, St. Augustine, Trinidad and Tobago. Jonas.Addae@sta.uwi.edu
authors.forename: Jonas I
authors.initials: JI
authors.lastname: Addae
authors.forename: Nakisha
authors.initials: N
authors.lastname: Ali
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Stone
mesh_terms: D000818:Animals; D002719:Chlormethiazole / Q000494:pharmacology*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D019579:Neocortex / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018757:GABA Modulators; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D002719:Chlormethiazole; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid