Citation

García-Sevilla JA, Ventayol P, Perez V, Rubovszky G, Puigdemont D, Ferrer-Alcón M, Andreoli A, Guimón J, Álvarez E. Neuropsychopharmacology 2004; 29(3): 580-588.

Copyright

(Copyright © 2004, Nature Publishing Group)

DOI

10.1038/sj.npp.1300356

PMID

14628003

Abstract

Major depression is associated with the upregulation of alpha(2A)-adrenoceptors in brain tissue and blood platelets. The homologous regulation of these receptors by G-protein-coupled receptor kinases (GRKs) might play a relevant role in the pathogenesis and treatment of depression. This study was designed to assess the status of the complex alpha(2A)-adrenoceptor/Galphai/GRK 2 in the platelets of depressed patients (n=22) before and after treatment with the antidepressant mirtazapine, an antagonist at alpha(2A)-adrenoceptors (30-45 mg/day for up to 6 months). A second series of depressed suicide attempters (n=32) were also investigated to further assess the status of platelet GRK 2 and GRK 6. Platelet alpha(2A)-adrenoceptors and Galphai protein immunoreactivities were increased in depressed patients (49 and 35%) compared with matched controls. In contrast, GRK 2 content was decreased in the two series of depressed patients (27 and 28%). GRK 6 (a GRK with different properties) was found unchanged. In drug-free depressed patients, the severity of depression (behavioral ratings with two different instruments) correlated inversely with the content of platelet GRK 2 (r=-0.46, n=22, p=0.032, and r=-0.55, n=22, p=0.009). After 4-24 weeks of treatment, mirtazapine induced downregulation of platelet alpha(2A)-adrenoceptors (up to 34%) and Galphai proteins (up to 28%), and the upregulation of GRK 2 (up to 30%). The results indicate that major depression is associated with reduced platelet GRK 2, suggesting that a defect of this kinase may contribute to the observed upregulation of alpha(2A)-adrenoceptors. Moreover, treatment with mirtazapine reversed this abnormality and induced downregulation of alpha(2A)-adrenoceptor/Galphai complex. The results support a role of supersensitive alpha(2A)-adrenoceptors in the pathogenesis and treatment of major depression.

Language: en

Keywords

Adult; Analysis of Variance; beta-Adrenergic Receptor Kinases; Blood Platelets; Chi-Square Distribution; Cyclic AMP-Dependent Protein Kinases; Depressive Disorder, Major; Female; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Male; Mianserin; Middle Aged; Mirtazapine; Receptor, Adenosine A2A; Suicide, Attempted