title: Electrically evoked synaptosomal amino acid transmitter release in human brain in alcohol misuse.
abstract: Severe chronic alcohol misuse leads to neuropathological changes in human brain, with the greatest neuronal loss in the dorsolateral prefrontal cortex. In this region, GABA(A) receptors are selectively upregulated, and show altered subunit expression profiles only in alcoholics without comorbid disease, whereas glutamate(NMDA) subunit expression profiles are selectively downregulated only in alcoholics with comorbid cirrhosis of the liver. To determine whether these outcomes might be conditional on synaptic transmitter levels, evoked release was studied in well-characterized synaptosome suspensions preloaded with L-[(3)H]glutamate and [(14)C]GABA and stimulated electrically (±10 V contiguous square waves, 0.4 ms, 100 Hz, 1.5 min) with and without Ca(2+). Stimulation elicited brief peaks of both radioisotopes that were larger in the presence of Ca(2+) ions (p < 0.01). A repeat stimulus evoked a second, smaller (p < 0.01) peak. Ca(2+)-dependent L-[(3)H]glutamate release, but not [(14)C]GABA release, was higher overall in alcoholics than in controls (p < 0.05). With comorbid cirrhosis, L-[(3)H]glutamate release showed a graded response, whereas [(14)C]GABA release was lowest in noncirrhotic alcoholics. Release patterns did not differ between cortical regions, or between males and females. Neither age nor postmortem interval was a significant confounder. The released transmitters may differentially alter receptor profiles on postsynaptic cells.
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Qld., Australia.
authors.forename: Sheng-Wen
authors.initials: SW
authors.lastname: Kuo
authors.forename: Peter R
authors.initials: PR
authors.lastname: Dodd
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000473:pathology*; D000596:Amino Acids / Q000378:metabolism*; D000704:Analysis of Variance; D019540:Area Under Curve; D001703:Biophysics; D001921:Brain / Q000473:pathology / Q000648:ultrastructure*; D002118:Calcium / Q000494:pharmacology; D002247:Carbon Isotopes / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007554:Isotopes / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D013997:Time Factors; D055815:Young Adult
chemical_list: D000596:Amino Acids; D002247:Carbon Isotopes; D007554:Isotopes; D002118:Calcium