Beta-arrestin-1 levels: reduced in leukocytes of patients with depression and elevated by antidepressants in rat brain.
OBJECTIVE
Beta-arrestins play a pivotal role in G protein-coupled receptor desensitization. beta-Arrestins interfere in G protein receptor interaction, thus leading to desensitization of G protein-mediated receptor signaling. G protein receptor signaling and its desensitization were previously implicated in the pathophysiology of mood disorders and in the mechanism of action of antidepressant and mood-stabilizing treatments. The present study aims at quantitatively evaluating beta-arrestin-1 levels in leukocytes of patients with major depression and the effect of antidepressants on beta-arrestin-1 levels in rat brain.


METHODS
Beta-arrestin-1 measurements were carried out in cortical, hippocampal, and striatal brain regions of rats chronically intragastrically treated with either imipramine, desipramine, or fluvoxamine. Similar measurements were conducted in mononuclear leukocytes of 36 untreated patients with major depression and 32 healthy volunteer subjects. Beta-arrestin-1 levels were evaluated through immunoblot analyses using monoclonal antibodies to beta-arrestin-1.


RESULTS
Beta-arrestin-1 levels were significantly elevated by all three antidepressants in rat cortex and hippocampus, while in the striatum no alterations could be detected. This process became significant within 10 days and took 2-3 weeks to reach maximal increase. Mononuclear leukocytes of patients with depression showed significantly reduced immunoreactive quantities of beta-arrestin-1. The reduction in beta-arrestin-1 levels was significantly correlated with the severity of depressive symptoms.


CONCLUSIONS
The findings in the rat study suggest beta-arrestin-1 elevation as a biochemical mechanism for antidepressant-induced receptor down-regulation. The findings in human subjects support the implication of beta-arrestin-1 in the pathophysiology of mood disorders. Beta-arrestin-1 measurements in patients with depression may potentially serve as a biochemical marker for depression.
Avissar
Sofia
S
Department of Clinical Pharmacology, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, ISRAEL. sofia@bgumail.bgu.ac.il
Matuzany-Ruban
Angela
A
Tzukert
Keren
K
Schreiber
Gabriel
G
D000328:Adult; D000368:Aged; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019390:Arrestins / Q000032:analysis* / Q000097:blood* / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D003866:Depressive Disorder / Q000097:blood / Q000175:diagnosis*; D003891:Desipramine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000737:chemistry* / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000187:drug effects; D012720:Severity of Illness Index; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D000928:Antidepressive Agents; C000605256:Arrb1 protein, rat; D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D016666:Fluvoxamine; D007099:Imipramine; D003891:Desipramine