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

Studies suggest α(2A)-adrenoceptors (α(2A)AR) dysregulation in major depressive disorder (MDD). Platelet α(2A)ARs exist in high- and low-conformational states that are regulated by G(i) protein. Although α(2A)AR coupling to G(i) protein plays an important role in signal transduction and is modulated by antidepressants, it has not been previously investigated. α₂AR 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(2A)AR 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(2A)AR coupling or density in treatment non-responders. Increased α(2A)AR 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. Copyright (C) 1999 Elsevier Science Ireland Ltd.