Cyclic AMP Second-Messenger Signal Amplification in Depression

Abstract

Beta-adrenergic-mediated cyclic AMP accumulation was reduced in lymphocytes obtained from depressed patients from that observed in an age- and sex-matched group of control subjects. Among the depressed patients, those not responding to treatment showed significantly lower pretreatment responses to isoproterenol compared with patients who exhibited significant clinical improvement during antidepressant treatment. Late-night (terminal) insomnia was significantly associated with the blunted response to beta-adrenergic stimulation. In depressed patients with the lowest isoproterenol response, the effect of forskolin (which acts distal to the receptor and directly stimulates the catalytic subunit) on cyclic AMP accumulation was also significantly decreased. This suggests that post-receptor modulations of signal amplification also play a role in the reduced response to beta-adrenergic stimulation in depression.

Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression

“…Indeed, reduced levels of the β-adrenergic receptor were previously extensively described in mononuclear leukocytes of patients with unipolar and bipolar depression (40)(41)(42)(43)(44). However, our functional measures, together with the complementary immunoblot studies, suggest also direct, quantitative, and functional reductions in G s protein in mononuclear leukocytes of depressed patients at the postreceptor level that are in accordance with functional findings of reduced β-adrenergic-receptor-coupled adenylate cyclase activity in patients with depression (40,41,(45)(46)(47). Most evidence suggests that muscarinic receptor characteristics are not altered in patients with affective disorder (37).…”

The Concept of Dysregulated Signal Transduction and Gene Expression in the Pathophysiology of Mood Disorders

“…Initial studies of -ARs in depression were carried out by determining agonist-stimulated cAMP formation in leukocytes or lymphocytes of depressed patients and normal controls by our group [58] and other investigators [51,[59][60][61]. Pandey et al [58] found that NE-stimulated [ 3 H]cAMP accumulation was significantly lower in leukocytes of depressed or bipolar patients.…”

Post-receptor signaling pathways in the pathophysiology and treatment of mood disorders

“…Overall, the preponderance of the evidence suggests altered receptor and postreceptor sensitivity of the cAMP generating system in the absence of consistent alterations in the number of receptors themselves [33][34][35][36][37]. A recent study found higher levels of cAMP-stimulated phosphorylation of a substrate protein (subsequently identified as Rap1) in platelets obtained from treated euthymic BPD patients compared with healthy subjects [38].…”