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Implications of the cAMP Signaling Pathway in Psychiatric Disorders: A Systematic Review of the Evidence

Published online by Cambridge University Press:  07 November 2014

Abstract

The last decade has seen a shift in the theoretical framework addressing the pathophysiology of psychiatric disorders. During this period, research endeavors have been directed toward investigating the biochemical mechanisms involved in the transduction of information from the cell surface to the cell interior. The emerging picture, supported by growing evidence, is that in addition to neurotransmitters and their receptors, various signal transduction pathways may be linked to the pathophysiology of major psychiatric disorders. In this review, the role of one such pathway—the cyclic adenosine monophosphate (cAMP) signaling pathway—will be highlighted. We review data suggesting the involvement of the upstream and downstream components of this system in the pathophysiology of psychiatric disorders.

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Feature Article
Copyright
Copyright © Cambridge University Press 2001

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References

REFERENCES

1.Duman, RS, Nestler, EJ. Signal transduction pathways for catecholamine receptors. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press, Ltd; 1995:303320.Google Scholar
2.Hyman, SE, Nestler, EJ. Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am J Psychiatry. 1996;153:151162.Google ScholarPubMed
3.Duman, RS, Heninger, GR, Nestler, EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54:597606.CrossRefGoogle ScholarPubMed
4.Kandel, ER. A new intellectual framework for psychiatry. Am J Psychiatry. 1998;155:457469.CrossRefGoogle ScholarPubMed
5.Manji, HK. G proteins: implications for psychiatry. Am J Psychiatry. 1992;149:746760.Google ScholarPubMed
6.Hudson, CJ, Young, LT, Li, PP, Warsh, JJ. CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia. Synapse. 1993;13:278293.CrossRefGoogle ScholarPubMed
7.Manji, HK, Potter, WZ, Lenox, RH. Signal transduction pathways: molecular targets for lithium's actions. Arch Gen Psychiatry. 1995;52:531543.CrossRefGoogle ScholarPubMed
8.Warsh, JJ, Li, PP. Second messenger systems and mood disorders. Current Opinion in Psychiatry. 1996;9:2329.CrossRefGoogle Scholar
9.Perez, J, Tardito, D, Mori, S, Racagni, G, Smeraldi, E, Zanardi, R. Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment. Bipolar Disord. 2000;2:2736.CrossRefGoogle ScholarPubMed
10.Young, LT, Li, PP, Kish, SJ, Siv, KP, Warsh, JJ. Postmortem cerebral cortex Gαs subunit levels are elevated in bipolar affective disorder. Brain Res. 1991;553:323326.CrossRefGoogle Scholar
11.Young, LT, Li, PP, Kish, SJ, et al.Cerebral cortex Gαs protein levels and forskolin-stimulated cAMP formation are increased in bipolar affective disorders. J Neurochem. 1993;61:890898.CrossRefGoogle Scholar
12.Friedman, E, Wang, HY. Receptor-mediated activation of G proteins is increased in postmortem brain of bipolar affective disorder subjects. J Neurochem. 1996;67:11451152.CrossRefGoogle ScholarPubMed
13.Ozawa, H, Gsell, W, Frolich, L. Imbalance of the Gs and Gi/o function in post-mortem human brain of depressed patients. J Neural Transm Gen Sect. 1993;94:6369.CrossRefGoogle Scholar
14.Pacheco, MA, Stockmeier, C, Meltzer, HY, Overholser, JC, Dilley, GE, Jope, RS. Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain. Brain Res. 1996;723:3745.CrossRefGoogle ScholarPubMed
15.Garcia-Sevilla, JA, Escriba, PV, Ozaita, A, et al.Up-regulation of immunolabelled a2A-adrenoreceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides. J Neurochem. 1999;72:282291.CrossRefGoogle ScholarPubMed
16.Cowburn, RF, Marcusson, JO, Eriksson, A, Wiehager, B, O'Neill, C. Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims. Brain Res. 1994;633:297304.CrossRefGoogle ScholarPubMed
17.Lowther, S, Crompton, MR, Katona, CLE, Horton, RW. GTPgS and forskolin-stimulated adenylyl cyclase activity in postmortem brain from depressed suicides and controls. Mol Psychiatry. 1996;1:470477.Google Scholar
18.Schreiber, G, Avissar, S, Danon, A, Belmaker, RH. Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry. 1991;92:273280.CrossRefGoogle Scholar
19.Young, LT, Li, PP, Kamble, A, Siu, KP, Warsh, JJ. Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder. Am J Psychiatry. 1994;151:594596.Google ScholarPubMed
20.Manji, HK, Chen, G, Shimon, H, Hsiao, JK, Potter, WZ, Belmaker, RH. Guanine nucleotide-binding proteins in bipolar affective disorder. Effects of long-term lithium treatment. Arch Gen Psychiatry. 1995;52:135144.CrossRefGoogle ScholarPubMed
21.Mitchell, PB, Manji, HK, Chen, G, et al.High levels of Gαs in platelets of euthymic patients with bipolar affective disorder. Am J Psychiatry. 1997;154:218223.Google Scholar
22.Avissar, S, Nechamkin, Y, Barki-Harrington, L, Roitman, G, Schreiber, G. Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent. J Affect Disord. 1997;43:8593.CrossRefGoogle ScholarPubMed
23.Avissar, S, Nechamkin, Y, Barki-Harrington, L, Roitman, G, Schreiber, G. Reduced G protein functions and immunoreactivity levels in mononuclear leukocytes of patients with depression. Am J Psychiatry. 1997;154:211217.Google ScholarPubMed
24.Avissar, S, Nechamkin, Y, Roitman, G, Schreiber, G. Dynamics of ECT normalization of low G protein function and immunoreactivity in mononuclear leukocytes of patients with major depression. Am J Psychiatry. 1998;155:666671.CrossRefGoogle Scholar
25.Avissar, S, Schreiber, G, Nechamkin, Y, et al.The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder. Arch Gen Psychiatry. 1999;56:178183.CrossRefGoogle Scholar
26.Garcia-Sevilla, JA, Walzer, C, Busquets, X, Escriba, PV, Balant, L, Guimón, J. Density of guanine nucleotide-binding proteins in platelets of patients with major depression: increased abundance of the Gαi2 subunit and down-regulation by antidepressant drug treatment. Biol Psychiatry. 1997:42:704712.CrossRefGoogle Scholar
27.Mann, JJ, Halper, JP, Wilner, PJ, et al.Subsensitivity of adenylyl cyclase-coupled receptors on mononuclear leukocytes from drug-free inpatients with a major depressive episode. Biol Psychiatry. 1997;42:859870.CrossRefGoogle ScholarPubMed
28.Menninger, JA, Tabakoff, B. Forskolin-stimulated platelet adenylyl cyclase activity is lower in a person with major depression. Biol Psychiatry. 1997;42:3038.CrossRefGoogle Scholar
29.Mooney, JJ, Samson, JA, McHale, NL, et al.Signal transduction by platelet adenylate cyclase: alterations in depressed patients may reflect impairment in the coordinate integration of cellular signals (coincidence detection). Biol Psychiatry. 1998;43:574583.CrossRefGoogle ScholarPubMed
30.Young, LT, Asghari, V, Li, PP, Kish, SJ, Fahnestock, M, Warsh, JJ. Stimulatory G-protein alpha-subunit mRNA levels are not increased in autopsied cerebral cortex from patients with bipolar disorder. Brain Res Mol Brain Res. 1996;42:4550.CrossRefGoogle Scholar
31.Spleiss, O, van Calker, D, Scharer, L, Adamovic, K, Berger, M, Gebicke-Haerter, PJ. Abnormal G protein alpha(s)-and alpha(i2)-subunit mRNA expression in bipolar affective disorder. Mol Psychiatry. 1998;3:512520.CrossRefGoogle ScholarPubMed
32.Gejman, PV, Martinez, M, Cao, Q, et al.Linkage analysis of fifty-seven microsatellite loci to bipolar disorder. Neuropsychopharmacol. 1993;9:3140.CrossRefGoogle ScholarPubMed
33.Le, F, Mitchell, P, Vivero, C, et al.Exclusion of close linkage of bipolar disorder to the Gs-a subunit gene in nine Australian pedigrees. J Affect Disord. 1994;32:187195.CrossRefGoogle Scholar
34.Ram, A, Guedj, F, Cravchik, A, et al.No abnormality in the gene for the G protein stimulatory alpha subunit in patients with bipolar disorder. Arch Gen Psychiatry. 1997;54:4448.CrossRefGoogle Scholar
35.Berrettini, WH, Ferraro, TN, Goldin, LR, et al.Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. Proc Natl Acad Sci U S A. 1994;91:58195821.Google ScholarPubMed
36.Berrettini, WH, Vuoristo, J, Ferraro, TN, Buono, RJ, Wildenauer, D, Ala-Kokko, L. Human G(olf) gene polymorphisms and vulnerability to bipolar disorder. Psychiatry Genet. 1998;8:235238.CrossRefGoogle Scholar
37.Okada, F, Crow, TJ, Roberts, GW. G protein (Gi, Go) in the medial temporal lobe in schizophrenia. Preliminary report of a neurochemical correlate of structural change. J Neural Transm Gen Sect. 1991;84:147153.CrossRefGoogle ScholarPubMed
38.Nishino, N, Kitamura, N, Hashimoto, T, et al.Increase in [3H]cAMP binding sites and decrease in Giα and Goα immunoreactivities in left temporal cortices from patients with schizophrenia. Brain Res. 1993;615:4149.CrossRefGoogle Scholar
39.Yang, CQ, Kitamura, N, Nishino, N, Shirakawa, O, Nakai, H. Isotype-specific G protein abnormalities in the left superior temporal cortex and limbic structures of patients with chronic schizophrenia. Biol Psychiatry. 1998;43:1219.CrossRefGoogle ScholarPubMed
40.Kerwin, RW, Beats, BC. Increased forskolin binding in the left parahippocampal gyrus and CA1 region in post mortem schizophrenic brain determined by quantitative autoradiography. Neurosci Lett. 1990;118:164168.CrossRefGoogle ScholarPubMed
41.Natsukari, N, Kulaga, H, Baker, I, Wyatt, RJ, Masserano, JM. Increased cyclic AMP response to forskolin in Epstein-Barr virus transformed human B-lymphocytes derived from schizophrenics. Psychopharmacol. 1997;130:235241.CrossRefGoogle ScholarPubMed
42.Stein, MB, Chen, G, Potter, WZ, Manji, HK. G-protein level quantification in platelets and leukocytes from patients with panic disorder. Neuropsychopharmacol. 1996;15:180186.CrossRefGoogle ScholarPubMed
43.Ozawa, H, Katamura, Y, Hatta, S, et al.Alterations of guanine nucleotide-binding proteins in postmortem human brain in alcoholics. Brain Res. 1993;620:174179.CrossRefGoogle ScholarPubMed
44.Waltman, C, Levine, MA, McCaul, ME, Svikis, DS, Wand, GS. Enhanced expression of the inhibitory protein Gi2 alpha and decreased activity of adenylyl cyclase in lymphocytes of abstinent alcoholics. Alcohol Clin Exp Res. 1993;17:315320.CrossRefGoogle ScholarPubMed
45.Saito, T, Ozawa, H, Katamura, Y, Hatta, S, Takahata, N, Riederer, P. Alterations of receptor-G-protein-adenylyl cyclase coupling in alcoholics. Alcohol Alcohol. 1994;2(suppl):211215.Google ScholarPubMed
46.Saito, T, Katamura, Y, Ozawa, H, Hatta, S, Takahata, N. Platelet GTP-binding protein in long-term abstinent alcoholics with an alcoholic first-degree relative. Biol Psychiatry. 1994;36:495497.CrossRefGoogle ScholarPubMed
47.Ozawa, H, Saito, T, Hatta, S, Hashimoto, E, Froelich, L, Ohshika, H, Takahata, N, Riederer, P. Reduced sensitivity to ethanol of Gs alpha and Gi/o alpha in the cerebral cortex of alcoholic patients. Alcohol Alcohol. 1994;29:9397.Google ScholarPubMed
48.Parsian, A, Todd, RD, Cloninger, CR, et al.Platelet adenylyl cyclase activity in alcoholics and subtypes of alcoholics. WHO/ISBRA Study Clinical Centers. Alcohol Clin Exp Res. 1996;20:745751.CrossRefGoogle ScholarPubMed
49.Jope, RS, Song, L, Grimes, CA, et al.Selective increases in phosphoinositide signaling activity and G protein levels in postmortem brain from subjects with schizophrenia or alcohol dependence. J Neurochem. 1998;70:763771.CrossRefGoogle ScholarPubMed
50.Ratsma, JE, Gunning, WB, Leurs, R, Schoffelmeer, AN. Platelet adenylyl cyclase activity as a biochemical trait marker for predisposition to alcoholism. Alcohol Clin Exp Res. 1999;23;600604.CrossRefGoogle ScholarPubMed
51.Escriba, PV, Sastre, M, Garcia-Sevilla, JA. Increased density of guanine nucleotide-binding proteins in the postmortem brains of heroin addicts. Arch Gen Psychiatry. 1994;51:494501.CrossRefGoogle ScholarPubMed
52.Garcia-Sevilla, JA, Ventayol, P, Busquets, X, La Harpe, R, Walzer, C, Guimon, J. Regulation of immunolabelled muopioid receptors and protein kinase C-alpha and zeta isoforms in the frontal cortex of human opiate addicts. Neurosci Lett. 1997;226:2932.CrossRefGoogle ScholarPubMed
53.Manji, HK, Chen, G, Potter, W, Kosten, TR. Guanine nucleotide binding proteins in opioid-dependent patients. Biol Psychiatry. 1997;41:130134.CrossRefGoogle ScholarPubMed
54.Perez, J, Zanardi, R, Mori, S, Gasperini, M, Smeraldi, E, Racagni, G. Abnormalities of cAMP-dependent endogenous phosphorylation in platelets from patients with bipolar disorder. Am J Psychiatry. 1995;152:12041206.Google ScholarPubMed
55.Zanardi, R, Racagni, G, Smeraldi, E, Perez, J. Differential effects of lithium on platelet protein phosphorylation in bipolar patients and healthy subjects. Psychopharmacol. 1997;129:4447.CrossRefGoogle ScholarPubMed
56.Perez, J, Tardito, D, Mori, S, Racagni, G, Smeraldi, E, Zanardi, R. Altered rapl endogenous phosphorylation and levels in platelets from patients with bipolar disorder. J Psychiatric Res. 2000;34:99104.CrossRefGoogle Scholar
57.Perez, J, Tardito, D, Mori, S, Racagni, G, Smeraldi, E, Zanardi, R. Abnormalities of cylic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder. Arch Gen Psychiatry. 1999;56:248253.CrossRefGoogle Scholar
58.Rahman, S, Li, PP, Young, T, Kofman, O, Kish, SJ, Warsh, JJ. Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder. J Neurochem. 1997;68:297304.CrossRefGoogle ScholarPubMed
59.Fields, A, Li, PP, Kish, SJ, Warsh, JJ. Increased cyclic AMP-dependent protein kinase activity in postmortem brain from patients with bipolar affective disorder. J Neurochem. 1999;73:17041710.CrossRefGoogle ScholarPubMed
60.Shelton, RC, Manier, DH, Sulser, F. cAMP-dependent protein kinase activity in major depression. Am J Psychiatry. 1996;153:10371042.Google ScholarPubMed
61.Manier, DH, Eiring, A, Shelton, RC, Sulser, F. b-adrenoreceptor-linked protein kinase A (PKA) activity in human fibroblasts from normal subjects and from patients with major depression. Neuropsychopharmacol. 1996;15:555561.CrossRefGoogle ScholarPubMed
62.Shelton, RC, Manier, DH, Peterson, CS, Ellis, TC, Sulser, F. Cyclic AMP-dependent protein kinase activity in subtypes of major depression and normal volunteers. Int J Neuropsychopharm. 1999;2:187192.CrossRefGoogle ScholarPubMed
63.Lowther, S, Katona, CLE, Crompton, MR, Horton, RW. Brain [3H]cAMP binding sites are unaltered in depressed suicides, but decreased by antidepressants. Brain Res. 1997;758:223228.CrossRefGoogle ScholarPubMed
64.Dwivedi, Y, Conley, R, Roberts, R, Tamminga, C, Faludi, G, Pandey, GN. Reduced [3H] cyclic AMP binding sites and PKA activity in the prefrontal cortex of suicide subjects. Abstr Soc Neurosci. 1999;839:2097.Google Scholar
65.Perez, J, Tardito, D, Racagni, G, Smeraldi, E, Zanardi, R. Protein kinase A and Rapl levels in platelets of untreated patients with major depression. Mol Psychiatry. 2001;6:4449.CrossRefGoogle Scholar
66.Dowlatshahi, D, MacQueen, GM, Wang, JF, Young, LT. Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet. 1998;352:17541755.Google ScholarPubMed
67.Dowlatshahi, D, MacQueen, GM, Wang, JF, Reiach, JS, Young, TL. G protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders: effects of diagnosis, suicide, and treatment at the time of death. J Neurochem. 1999;73:11211126.CrossRefGoogle ScholarPubMed
68.Musselman, DL, Tomer, A, Manatunga, AK, et al.Exaggerated platelet reactivity in major depression. Am J Psychiatry. 1996;153:13131317.Google ScholarPubMed
69.Alexopoulos, GS, Meyers, BS, Young, RC, Campbell, S, Silbersweig, D, Charlson, M. “Vascular depression” hypothesis. Arch Gen Psychiatry. 1997;54:915922.CrossRefGoogle ScholarPubMed
70.Musselman, DL, Evans, DL, Nemeroff, CB. The relationship of depression to cardiovascular disease. Arch Gen Psychiatry. 1998;55:580592.CrossRefGoogle ScholarPubMed
71.Ford, DE, Mead, LA, Chang, PP, Cooper-Patrick, L, Wang, NY, Klag, MJ. Depression is a risk factor for coronary artery disease in men. Arch Intern Med. 1998;158:14221426.CrossRefGoogle ScholarPubMed
72.Tardito, D, Tura, GB, Bocchio, L, et al.Abnormal levels of cAMP-dependent protein kinase regulatory subunits in platelets from patients with schizophrenia. Neuropsychopharmacol. 2000;23:216219.CrossRefGoogle Scholar
73.Kawanishi, Y, Harada, S, Tachikawa, H, Okubo, T, Shiraishi, H. Novel variants in the promoter region of the CREB gene in schizophrenic patients. J Hum Genet. 1999;44:428430.CrossRefGoogle ScholarPubMed
74.Perez, J, Tardito, D, Ravizza, L, Racagni, G, Mori, S, Maina, G. Altered cAMP-dependent protein kinase A in platelets of patients with obsessive-compulsive disorder. Am J Psychiatry. 2000;157:284286.CrossRefGoogle ScholarPubMed
75.Manji, HK, Lenox, RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry. 2000;48:518530.CrossRefGoogle ScholarPubMed
76.Adams, MR, Brandon, EP, Chartoff, EH, Idzerda, RL, Dorsa, DM, McKnight, GS. Loss of haloperidol-induced gene expression and catalepsy in protein kinase A-deficient mice. Proc Natl Acad Sci U S A. 1997;94:1215712161.CrossRefGoogle ScholarPubMed
77.Lidow, MS, Song, ZM, Castner, SA, Allen, PB, Greengard, P, Goldman-Raki, PS. Antipsychotic treatment induces alterations in dendrite- and spine-associated proteins in dopamine-rich areas of the primate cerebral cortex. Biol Psychiatry. 2001;49:112.CrossRefGoogle ScholarPubMed