RECEPTORS, ADENYLATE-CYCLASE, DEPRESSION, AND LITHIUM

  • 1 January 1981
    • journal article
    • research article
    • Vol. 16  (4) , 333-350
Abstract
Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline (norepinephrine, NA) in the brain, direct .beta.-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Newer theories of antidepressant action suggest that a reduction in .beta.-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than NA turnover changes. It is possible to evaluate the .beta.-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cAMP rise after adrenergic agonists. A clinical trial of the .beta.-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cAMP before treatment with salbutamol rose 267% in response to salbutamol 0.25 mg i.v. After 1 and 3 wk of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cAMP response to i.v. salbutamol declined over 60%. The .beta.-adrenergic adenylate cyclase remained subsensitive 4 days after cessation of salbutamol therapy. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data show that Li markedly reduces activity of .beta.-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cAMP response to s.c. epinephrine. The Li effect is specific, since the plasma cAMP response to glucagon is not inhibited. The plasma cGMP response to s.c. epinephrine, suggested as a model for presynaptic .alpha.-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cAMP and cGMP may be viewed as balancing substances, their interaction may provide a mechanism for Li''s dual clinical effects in mania and depression. It is important that in vivo techniques be developed for evaluating receptor changes. The plasma cAMP response to adrenergic stimulation provides an in vivo measure of receptor function that can be useful in studying drug effects during the clinical treatment of humans.