Regulation of platelet α<inf>2A</inf>-adrenoceptors, Gi proteins and receptor kinases in major depression: Effects of mirtazapine treatment

Jesús A. García-Sevilla, Pedro Ventayol, Víctor Pérez, Grégoire Rubovszky, Dolors Puigdemont, Marcel Ferrer-Alcón, Antonio Andreoli, José Guimón, Enric Alvarez

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34 Citations (Scopus)

Abstract

Major depression is associated with the upregulation of α 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 α 2A-adrenoceptor/Gαi/GRK 2 in the platelets of depressed patients (n = 22) before and after treatment with the antidepressant mirtazapine, an antagonist at α2A-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 α2A-adrenoceptors and Gαi 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 α2A-adrenoceptors (up to 34%) and Gαi 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 α2A-adrenoceptors. Moreover, treatment with mirtazapine reversed this abnormality and induced downregulation of α2A-adrenoceptor/Gαi complex. The results support a role of supersensitive α2A-adrenoceptors in the pathogenesis and treatment of major depression.
Original languageEnglish
Pages (from-to)580-588
JournalNeuropsychopharmacology
Volume29
Issue number3
DOIs
Publication statusPublished - 1 Mar 2004

Keywords

  • α - adrenoceptors 2A
  • Blood platelets
  • Gi proteins
  • GRK 2/6
  • Major depression
  • Mirtazapine

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