Summary
It is suggested that affective disorders arise from the dysbalance of the two major intraneuronal signal amplification systems, the adenylate cyclase and the phospholipase C system, with depression resulting from underfunction of cyclic adenosine 3′,5′-monophosphate-mediated effector cell responses associated with an absolute or relative dominance of the inositoltriphosphate/ diacylglycerol-mediated responses and mania resulting from the converse. The usefulness of this hypothesis is discussed with respect to (a) the mechanism of action of current therapeutic agents and (b) the development of novel therapeutic approaches.
Similar content being viewed by others
References
Abdulla YH, Hamadah K (1970) 3′,5′ cyclic adenosine monophosphate in depression and mania. Lancet 1: 378–381
Andersen PH, Klysner R, Geisler A (1984) Fluoride-stimulated adenylate cyclase activity in rat brain following chronic treatment with psychotropic drugs. Neuropharmacology 23: 445–447
Berridge MJ (1984) Inositol triphosphate and diacylglycerol as second messengers. Biochem J 220: 345–360
Codina J, Hildebrandt J, Sunyer T, Sekura RD, Manclark CR, Iyengar R, Birnbaumer L (1984) Mechanisms in the vectorial receptor-adenylate cyclase signal transduction. Adv Cyclic Nucleotide Protein Phosphorylation Res 17: 111–125
Coppen A (1967) The biochemistry of affective disorders. Br J Psychiatry 113: 1237–1264
Dousa T, Hechter O (1970) Lithium and brain adenyle cyclase. Lancet 1: 834–835
Ebstein RP, Oppenheim G, Ebstein BS, Amiri Z, Stessman J (1986) The cyclic AMP second messenger system in man: The effect of heredity, hormones, drugs, aluminum, age and disease on signal amplification. Prog Neuropsychopharmacol Biol Psychiatry 10: 323–353
Extein I, Tallman J, Smith CC, Goodwin FK (1979) Changes in lymphocyte beta-adrenergic receptors in depression and mania. Psychiatry Res 1: 191–197
Guiot-Goffioul F, Gerard-Vanderhove MA, Troisfontaines B, Breulet M, von Frenckell R, Bobon D (1987) Preliminary results of a double-blind study between rolipram and desimipramine in hospitalized patients with major depressive symptoms. Acta Psychiatr Belg 87: 230–235
Hallcher LM, Sherman WR (1980) The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 225: 10896–10901
Horowski R, Sastre-y-Hernandez M (1985) Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients: global evaluation of the preliminary reports. Curr Ther Res 38: 23–29
Janowsky DS, El-Yousef MK, Davis JM, Sekerke HJ (1972) A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2: 632–635
Janowsky DS, Risch SC (1984) Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders and stress. Drug Develop Res 4: 125–142
Kaspar S, Moises HW, Beckmann H (1981) The anticholinergic biperiden in depressive disorders. Pharmacopsychiatry 14: 195–198
Khan MC, Wickham EA, Reed JV (1987) Lithium versus placebo in acute depression: á clinical trial. Int Clin Psychopharmacol 2: 47–54
Krebs EG, Beavo JA (1979) Phosphorylation-dephosphorylation of enzymes. Ann Rev Biochem 48: 923–959
Levin RM, Weiss B (1976) Mechanism by which psychotropic drugs inhibit adenosine cyclic 3′,5′-monophosphate phosphodiesterase of brain. Mol Pharmacol 12: 581–589
Matthysse S (1986) Animal models in psychiatric research. Prog Brain Res 65: 259–270
Menkes DB, Rasenick MM, Wheeler MA, Bitensky MW (1983) Guanosine triphosphate activation of brain adenylate cyclase: Enhancement by long-term antidepressant treatment. Science 219: 65–67
Mork A, Geisler A (1987) Mode of action of lithium on the catalytic unit of adenylate cyclase from rat brain. Pharmacol Toxicol 60: 241–248
Namura S, Zorn SH, Enna SJ (1987) Selective interaction of tricyclic antidepressants with a subclass of rat brain cholinergic muscarinic receptors. Life Sci 40: 1751–1760
Newman ME, Klein E, Birmaher B, Feinsod M, Belmaker RH (1983) Lithium at therapeutic concentrations inhibits human brain noradrenaline-sensitive cyclic AMP accumulation. Brain Res 278: 380–381
Newman ME, Belmaker RH (1987) Effects of lithium in vitro and ex vivo on components of the adenylate cyclase system in membranes from the cerebral cortex of the rat. Neuropharmacology 26: 211–217
Newman ME, Lipot M, Lerer B (1987) Differential effects of chronic administration of desipramine on the cyclic AMP response in cortical slices and membranes in the rat. Neuropharmacology 26: 1127–1130
Nishizuka Y (1984) The role of protein kinase C in cell surface signal transduction and tumor promotion. Nature 308: 693–698
Ohno S, Kawasaki H, Imajoh S, Suzuki K (1987) Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature 325: 161–166
Ossofsky HJ (1976) Affective and atopic disorder and cyclic AMP. Compr Psychiatry 17: 335–346
Pandey G, Dysken MW, Garver DL (1979) Beta-adrenergic receptor function in affective illness. Am J Psychiatry 136: 675–678
Przegalinski E, Bigajska K (1983) Antidepressant properties of some phosphodiesterase inhibitors. Pol J Pharmacol Pharm 35: 233–240
Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am J Psychiatry 122: 509–522
Snyder SH, Yamamura HI (1977) Antidepressants and the muscarinic acetylcholine receptor. Arch Gen Psychiatry 34: 236–239
Stone EA (1983) Problems with current catecholamine hypotheses of antidepressant agents: Speculations leading to a new hypothesis. Behav Brain Sci 6: 535–577
Strada SJ, Martin MW, Thompson WJ (1984) General properties of multiple molecular forms of cyclic nucleotide phosphodiesterase in the nervous system. Adv Cyclic Nucleotide Protein Phosphorylation Res 16: 13–29
Sulser F (1983) Deamplification of noradrenergic signal transfer by antidepressants: a unified catecholamine-serotonin hypothesis of affective disorders. Psychopharmacol Bull 19: 300–304
Vetulani J, Sulser F (1975) Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic forebrain. Nature 257: 495–496
Wachtel H (1983) Potential antidepressant activity of rolipram and other selective cyclic adenosine 3′5′-monophosphate phosphodiesterase inhibitors. Neuropharmacology 22: 367–372
Wachtel H, Löschmann PA (1986) Effects of forskolin and cyclic nucleotides in animal model predictive of antidepressant activity: Interactions with rolipram. Psychopharmacology 90: 430–435
Willner P (1984) The ability of antidepressant drug to desensitize β-receptors is inversely correlated with their clinical potency. J Affective Disord 7: 53–58
Zeller E, Stief HJ, Pflug B, Sastre-y-Hernandez M (1984) Results of a phase II study of the antidepressant effect of rolipram. Pharmacopsychiatry 17: 188–120
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wachtel, H. Dysbalance of neuronal second messenger function in the aetiology of affective disorders: A pathophysiological concept hypothesising defects beyond first messenger receptors. J. Neural Transmission 75, 21–29 (1989). https://doi.org/10.1007/BF01250641
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01250641