Receptors, adenylate cyclase, depression, and lithium

R. H. Belmaker

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct β-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Moreover, newer theories of antidepressant action suggest that a reduction in β-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. It is possible to evaluate the β-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the β-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cyclic AMP before treatment with salbutamol rose 267% in response to salbutamol 0.25 mg iv. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma acyclic AMP response to iv salbutamol declined over 60%. The β-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 are presented that Li, too, markedly reduces activity of β-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. The plasma cyclic GMP response to subcutaneous epinephrine, suggested as a model for presynaptic α-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cyclic AMP and cyclic GMP may be viewed as balancing substance, 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 cyclic AMP 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.

Original languageEnglish
Pages (from-to)333-350
Number of pages18
JournalBiological Psychiatry
Volume16
Issue number4
StatePublished - 1 Jan 1981
Externally publishedYes

ASJC Scopus subject areas

  • Biological Psychiatry

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