Dysregulation of IRAS/nischarin and other potential I1-imidazoline receptors in major depression postmortem brain: Downregulation of basal contents by antidepressant drug treatments

Abstract

Background: Major depressive disorder (MDD) has been associated with altered brain densities of imidazoline receptors (I₁-IR and I₂-IR types).

Methods: The contents of potential I₁-IR IRAS/nischarin (167kDa) and, for comparison, those of I₁- (85kDa) and I₂- (45kDa and 30kDa) IR proteins were quantified by western blotting in postmortem prefrontal cortex (PFC/BA9) of antidepressant-free ([MDD(-)], n=9) and antidepressant-treated ([MDD(+)], n=12) subjects and matched controls (n=19).

Results: In MDD, regardless of antidepressant treatment (n=21), IRAS/nischarin was not altered in PFC/BA9. However, the content of IRAS/nischarin was found modestly and not significantly increased (+19%, p=0.075) in MDD(-) and significantly decreased (-24%, p=0.001) in MDD(+), revealing that basal I₁-IR content was downregulated by antidepressants. Putative 85kDa I₁-IR was upregulated (+35%, p=0.035) in MDD(-) but it was not reduced (-14%, p=0.37) in MDD(+). There was a positive correlation (r=0.33, p=0.037, n=40) between the contents of IRAS/nischarin and 85kDa IR proteins in PFC/BA9 (control and MDD subjects). In MDD and regardless of antidepressants, the content of cortical 45kDa I₂-IR was increased (+31%, p=0.006) and that of 30kDa I₂-IR decreased (-14%, p=0.002), indicating basal dysregulations of these potential IRs.

Limitations: MDD(+) subjects had been treated with a variety of antidepressant drugs. The results must be understood in the context of suicide victims with MDD.

Conclusions: The dysregulation of IRAS/nischarin in depressed brains is a major novel finding that supports a role of this potential I₁-IR in the neurobiology of MDD and in the molecular mechanisms of antidepressant drugs.

Keywords: Antidepressant drugs; IRAS/nischarin; Imidazoline receptors; Major depressive disorder; Postmortem human brain.