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

Studies suggest alpha(2A)-adrenoceptors (alpha(2A)AR) dysregulation in majo r depressive disorder (MDD). Platelet alpha(2A)ARs exist in high- and low-c onformational states that are regulated by G(i) protein. Although alpha(2A) AR coupling to G(i) protein plays an important role in signal transduction and is modulated by antidepressants, it has not been previously investigate d, alpha(2)AR density in the high- and low-conformational states, agonist a ffinity and coupling efficiency were investigated in 27 healthy control sub jects, 23 drug-free MDD patients and 16 patients after imipramine treatment using [H-3]yohimbine saturation and norepinephrine displacement of [H-3]yo himbine binding experiments. Coupling measures were derived from NE-displac ement experiments. Patients had significantly higher alpha(2A)AR density, p articularly in the high-conformational state, than control subjects. Coupli ng 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 negativ e treatment outcome. Imipramine induced uncoupling (-11%) and redistributio n of receptor density in treatment responders only, but had no effect on al pha(2A)AR coupling or density in treatment non-responders. Increased alpha( 2A)AR density may represent a trait marker in MDD. The results provide indi rect evidence for abnormal protein kinase A (PKA) and protein kinase C (PKC ) in MDD which may be pursued in future investigations. Published by Elsevi er Science Ireland Ltd.