Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder.

Abstract

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.

• Authors: Brian Dean, Elizabeth Scarr, Mark McLeod
• Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res) Vol. 138 Issue 2 Pg. 145-55 (Aug 18 2005) ISSN: 0169-328X [Print] Netherlands
• PMID: 15950312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GABA Agonists
• GABA Modulators
• Protein Subunits
• Pyridines
• Receptors, GABA-A
• Muscimol
• Flumazenil
• gamma-Aminobutyric Acid
• Clonazepam
• Zolpidem

Topics

• Adult
• Aged
• Binding, Competitive (drug effects, physiology)
• Bipolar Disorder (metabolism, physiopathology)
• Brain Chemistry (physiology)
• Clonazepam (metabolism, pharmacology)
• Female
• Flumazenil (metabolism, pharmacology)
• GABA Agonists (metabolism, pharmacology)
• GABA Modulators (metabolism, pharmacology)
• Hippocampus (metabolism, physiopathology)
• Humans
• Male
• Middle Aged
• Muscimol (metabolism, pharmacology)
• Protein Subunits (drug effects, metabolism)
• Pyridines (metabolism, pharmacology)
• Radioligand Assay
• Receptors, GABA-A (drug effects, metabolism)
• Schizophrenia (metabolism, physiopathology)
• Zolpidem
• gamma-Aminobutyric Acid (metabolism)