title: AMPA receptors on developing medial septum/diagonal band neurons are sensitive to early postnatal binge-like ethanol exposure.
abstract: The impact of binge-like, early postnatal ethanol treatment on AMPA or kainate whole cell currents was examined in acutely isolated medial septum/diagonal band (MS/DB) neurons. AMPA (10 or 100 microM) current was inhibited by GYKI 52466, a selective AMPA receptor (AMPAR) antagonist, in all neurons isolated on postnatal day (PD) 5-8, PD 12-15 or PD 32-35. Cyclothiazide, a selective inhibitor of AMPAR desensitization, also effectively potentiated AMPA currents. This suggests that non-NMDA, ionotropic glutamate receptors on immature MS/DB neuron are predominantly AMPARs. Concentration-dependent kainate (10-1000 microM) application evoked nondesensitizing currents that exhibited an increase in the maximum response by the end of first postnatal month, consistent with developmental regulation of AMPAR function. Acute 3 s ethanol application (100 mM) consistently blunted AMPA- and kainate currents approximately 20-30% across age groups. Inhibition was sustained during continuous ethanol superfusion lasting 10-12 min without evidence of acute tolerance. Repeated oral intubation of rat pups with ethanol (5.25 g/kg/day on PD 4-9), which models third trimester human binge drinking, resulted in peak blood ethanol levels of approximately 350 mg/dl (measured 90 min after PD 6 dosing). AMPA or kainate currents were upregulated in neurons isolated on PD 32-35 by earlier ethanol intubation suggesting that binge-like intoxication augments developing AMPAR function. Despite this augmentation of AMPAR function, no significant changes were found in the sensitivity of AMPA currents to GYKI 52466, cyclothiazide or acute ethanol (100 mM) sensitivity or in the levels of GluR1/GluR2 subunit proteins from MS/DB tissue. These results indicate that non-NMDA ionotrophic glutamate receptors on immature MS/DB neurons, which are largely of the AMPAR subtype, are moderately sensitive to immediate inhibition by ethanol. Repeating this inhibition during early postnatal binge-like intoxication can augment normal development of AMPAR function.
authors.affiliation: Department of Medical Pharmacology and Toxicology, Texas A&M University System Health Science Center, College of Medicine MS 1114, College Station, TX 77843-1114, USA.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Hsiao
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Frye
mesh_terms: D020268:Alcohol-Induced Disorders, Nervous System / Q000503:physiopathology*; D000435:Alcoholic Intoxication / Q000503:physiopathology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001569:Benzodiazepines; D001581:Benzothiadiazines / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D020667:Diagonal Band of Broca / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000503:physiopathology; D000431:Ethanol / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000959:Antihypertensive Agents; D001569:Benzodiazepines; D001581:Benzothiadiazines; D002492:Central Nervous System Depressants; D000431:Ethanol; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007608:Kainic Acid; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C061950:GYKI 52466; C104722:glutamate receptor ionotropic, AMPA 2; C004639:cyclothiazide