Dysregulation of IRAS/nischarin and other potential I1-imidazoline receptors in major depression postmortem brain: Downregulation of basal contents by antidepressant drug treatments.
Major depressive disorder (MDD) has been associated with altered brain densities of imidazoline receptors (I1-IR and I2-IR types).



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).



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.



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



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.
Laboratori de Neurofarmacologia, IUNICS/IdISPa, Universitat de les Illes Balears (UIB), Palma de Mallorca, Spain; Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain.
Benjamin
B
Keller
Laboratori de Neurofarmacologia, IUNICS/IdISPa, Universitat de les Illes Balears (UIB), Palma de Mallorca, Spain; Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain. Electronic address: jesus.garcia-sevilla@uib.es.
Jesús A
JA
García-Sevilla
D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D001344:Autopsy; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000188:drug therapy*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D054755:Imidazoline Receptors / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000187:drug effects; D013405:Suicide; D015854:Up-Regulation / Q000187:drug effects
D000928:Antidepressive Agents; D054755:Imidazoline Receptors; C410887:imidazoline I1 receptors
Antidepressant drugs; IRAS/nischarin; Imidazoline receptors; Major depressive disorder; Postmortem human brain