Platelet alpha 2A-adrenoceptor function in major depression: G i coupling, effects of imipramine and relationship to treatment outcome

Abstract

Studies suggest α 2A-adrenoceptors (α 2AAR) dysregulation in major depressive disorder (MDD). Platelet α 2AARs exist in high- and low-conformational states that are regulated by G i protein. Although α 2AAR coupling to G i protein plays an important role in signal transduction and is modulated by antidepressants, it has not been previously investigated. α 2AR density in the high- and low-conformational states, agonist affinity and coupling efficiency were investigated in 27 healthy control subjects, 23 drug-free MDD patients and 16 patients after imipramine treatment using 3H-yohimbine saturation and norepinephrine displacement of 3H-yohimbine binding experiments. Coupling measures were derived from NE-displacement experiments. Patients had significantly higher α 2AAR density, particularly in the high-conformational state, than control subjects. Coupling indices were normal in patients. High pre-treatment agonist affinity to the receptor in the high-conformational state and normal coupling predicted positive treatment outcome. Decreased coupling to G i predicted a negative treatment outcome. Imipramine induced uncoupling (−11%) and redistribution of receptor density in treatment responders only, but had no effect on α 2AAR coupling or density in treatment non-responders. Increased α 2AAR density may represent a trait marker in MDD. The results provide indirect evidence for abnormal protein kinase A (PKA) and protein kinase C (PKC) in MDD which may be pursued in future investigations.