Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder.
Postmortem CNS studies have suggested an uncoupling of the gamma-aminobutyric acid (GABA) and benzodiazepine binding sites on the hippocampal GABA(A) receptor in schizophrenia. The GABA(A) receptor is an assembly of discrete subunits that form a ligand-gated ion channel, the binding characteristics of which are defined by receptor subunit composition. Thus, a likely explanation for an uncoupling between the GABA and benzodiazepine binding sites on the GABA(A) receptor would be a change in receptor subunit composition. To test this hypothesis we measured the density of GABA ([(3)H]muscimol) and benzodiazepine ([(3)H]flumazenil) binding sites on the GABA(A) receptor in hippocampi, obtained postmortem, from schizophrenic, bipolar I disorder and control subjects. In addition, we measured the amount of [(3)H]flumazenil binding that could be displaced with zolpidem and clonazepam. Levels of both [(3)H]muscimol and [(3)H]flumazenil binding were significantly decreased in part of the CA2 from subjects with schizophrenia; the decrease in [(3)H]flumazenil being due to decreases in both zolpidem-sensitive and -insensitive radioligand binding. There were complex regionally specific changes in [(3)H]muscimol binding in the hippocampus from subjects with bipolar I disorder but there were no significant changes in the overall levels of [(3)H]flumazenil binding. There were significant decreases in zolpidem-sensitive and increases in zolpidem-insensitive [(3)H]flumazenil binding in most regions of the sections of the hippocampal formation studied in bipolar I disorder. Unlike [(3)H]flumazenil, zolpidem does not bind to the alpha5 subunit of the GABA(A) receptor; therefore, we postulate that there is an increase in GABA(A) receptors containing alpha5 subunit in the hippocampus from subjects with bipolar I disorder.
Dean
Brian
B
The Rebecca L. Cooper Research Laboratories, The Mental Health Research Institute of Victoria, Parkville, Victoria, Australia. bdean_mhri@iprimus.com.au
Scarr
Elizabeth
E
McLeod
Mark
M
D000328:Adult; D000368:Aged; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001714:Bipolar Disorder / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000502:physiology*; D002998:Clonazepam / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005442:Flumazenil / Q000378:metabolism / Q000494:pharmacology; D018755:GABA Agonists / Q000378:metabolism / Q000494:pharmacology; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009118:Muscimol / Q000378:metabolism / Q000494:pharmacology; D021122:Protein Subunits / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism* / Q000503:physiopathology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018755:GABA Agonists; D018757:GABA Modulators; D021122:Protein Subunits; D011725:Pyridines; D011963:Receptors, GABA-A; D009118:Muscimol; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D000077334:Zolpidem