cAMP Signal Transduction Abnormalities in the Pathophysiology of Mood Disorders: Contributions from Postmortem Brain Studies

  • Annisa Chang
  • Peter P. Li
  • Jerry J. Warsh
Part of the Neurobiological Foundation of Aberrant Behaviors book series (NFAB, volume 4)


During the past decade, considerable advances have been made in second messenger and signal transduction research in mood disorders. In this chapter, evidence derived from human postmortem brain studies is reviewed which supports the emerging view that postreceptor disturbances in G protein-linked cAMP signaling pathways play a major role in the pathophysiology of bipolar (BD) and major depressive disorders (MDD). In addition, the pathophysiological implications of the available evidence are also discussed, within the context of findings from recent neuroimaging and neuropathological studies.


Mood Disorder Postmortem Brain cAMP Response Element Binding cAMP Signaling Bipolar Affective Disorder 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Amieux PS, Cummings DE, Motamed K, Brandon EP, Wailes LA, Le K, Idzerda RL, McKnight GS. Compensatory regulation of Ria protein levels in protein kinase A mutant mice. J Biol Chem 1997; 272: 3993–3998.PubMedCrossRefGoogle Scholar
  2. Anand A, Chamey DS. Norepinephrine dysfunction in depression. J Clin Psychiatry 2000; 61: 16–24.PubMedCrossRefGoogle Scholar
  3. Andreopoulos S, Siu KP, Li PP, Warsh JJ. Reduced ADP-ribosylation of Gas in postmortem bipolar disorder temporal cortex. Biol Psychiatry 1997; 41: 61S.Google Scholar
  4. Andreopoulos S, Li PP, Siu KP, Warsh JJ. Characterization of as immunoreactive ADP- ribosylated proteins in postmortem human brain. J Neurosci Res 1999; 56: 632–643.PubMedCrossRefGoogle Scholar
  5. Berger AJ, Hart AC, Kaplan JM. Gas-induced neurodegeneration in Caenorhabditis elegans. J Neurosci 1998; 18: 2871–2880.PubMedGoogle Scholar
  6. Bornfeldt KE, Krebs EG. Crosstalk between protein kinase A and growth factor receptor signaling pathways in arterial smooth muscle. Cellular Signalling 1999; 11: 465–477.PubMedCrossRefGoogle Scholar
  7. Callado LF, Meana JJ, Grijalba B, Pazos A, Sastre M, Sastre M, Garcia-Sevilla JA. Selective increase of a7A-adrenoceptor agonist binding sites in brains of depressed suicide victims. J Neurochem 1998; 70: 1114–1123.PubMedCrossRefGoogle Scholar
  8. Chang A, Li PP, Kish S, Warsh JJ. Altered postmortem temporal cortex cAMP-dependent protein kinase subunit levels in bipolar disorder. Abst Soc Neurosci 2000; 26: 2314.Google Scholar
  9. Chang FH, Bourne HR. Cholera toxin induces cAMP-independent degradation of Gs. J Biol Chem 1989; 264: 5352–5357.PubMedGoogle Scholar
  10. Chen J, Rasenick MM. Chronic antidepressant treatment facilitates G protein activation of adenylyl cyclase without altering G protein content. J Pharmacol Exp Ther 1995; 275: 509–517.PubMedGoogle Scholar
  11. Chem Y. Regulation of adenylyl cyclase in the central nervous system. Cell Signal 2000; 12: 195–204.CrossRefGoogle Scholar
  12. Chuang TT, Iacovelli L, Sallese M, De Blasi A. G protein-coupled receptors: heterologous regulation of homologous desensitization and its implications. Trends Pharmacol Sci 1996; 17: 416–421.PubMedCrossRefGoogle Scholar
  13. Cotter D, Mackay D, Landau S, Kerwin R, Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 2001; 58: 545–53.PubMedCrossRefGoogle Scholar
  14. Cowbum 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: 297–304.CrossRefGoogle Scholar
  15. De A, Boyadjieva NI, Pastorcic M, Reddy BV, Sarkar DK. Cyclic AMP and ethanol interact to control apoptosis and differentiation in hypothalamic beta-endorphin neurons. J Biol Chem 1994; 269: 26697–26705.PubMedGoogle Scholar
  16. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL. Epac is a Rap 1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998; 396: 474–477.PubMedCrossRefGoogle Scholar
  17. Dowlatshahi D, MacQueen GM, Wang JF, Reiach JS, Young LT. 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: 1121–1126.PubMedCrossRefGoogle Scholar
  18. Drevets WC, Price JL, Simpson JR, Jr., Todd RD, Reich T, Vannier M, Raichle ME Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386: 824–827.PubMedCrossRefGoogle Scholar
  19. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry 2000; 48: 813–829.PubMedCrossRefGoogle Scholar
  20. Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 1999; 46: 1181–1191.PubMedCrossRefGoogle Scholar
  21. Duman RS, Malberg J, Nakagawa S, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry 2000; 48: 732–739.PubMedCrossRefGoogle Scholar
  22. Dwivedi Y, Pandey GN. Effects of subchronic administration of antidepressants and anxiolytics on levels of the alpha subunits of G proteins in the rat brain. J Neural Trans 1997; 104: 747–760.CrossRefGoogle Scholar
  23. Dwivedi Y, Conley R, Roberts R, Tamminga C, Faludi G, et al. Reduced [3H]cyclic AMP binding sites and PKA activity in the prefrontal cortex of suicide subjects. Abst Soc Neurosci 1999; 25: 2097.Google Scholar
  24. Dwivedi Y, Pandey GN. Adrenal glucocorticoids modulate [3H] cyclic AMP binding to protein kinase A (PKA), cyclic AMP-dependent PKA activity, and protein levels of selective regulatory and catalytic subunit isoforms of PKA in rat brain. J Pharmacol Exp Ther 2000; 294: 103–116.PubMedGoogle Scholar
  25. Emamghoreishi M, Warsh JJ, Sibony D, Li PP. Lack of effect of chronic antidepressant treatment on Gs and Gi a-subunit protein and mRNA levels in the rat cerebral cortex. Neuropsychopharmacolgy 1996; 15: 281–287.CrossRefGoogle Scholar
  26. Emamghoreishi M, Schlichter L, Li PP, Parikh S, Sen J, Kamble A, Warsh JJ. High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder. Am J Psychiatry 1997; 154: 976–982.PubMedGoogle Scholar
  27. Extein I, Tallman J, Smith CC, Goodwin FK. Changes in lymphocyte beta-adrenergic receptors in depression and mania. Psychiatry Res 1979; 1: 191–197.PubMedCrossRefGoogle Scholar
  28. 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: 1704–1710.PubMedCrossRefGoogle Scholar
  29. Friedman E, Wang HY. Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects. J Neurochem 1996; 67: 1145–1152.PubMedCrossRefGoogle Scholar
  30. Garcia-Sevilla JA, Escriba PV, Ozaita A, La Harpe R, Walzer C, Eytan A, Guimon J. Up-regulation of immunolabeled a2A-adrenoceptors, G, coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides. J Neurochem 1999; 72: 282–291.PubMedCrossRefGoogle Scholar
  31. Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 1989; 59: 675–680.PubMedCrossRefGoogle Scholar
  32. Gonzalez AM, Pascual J, Meana JJ, Barturen F, del Arco C, Pazos A, Garcia-Sevilla JA. Autoradiographic demonstration of increased a2-adrenoceptor agonist binding sites in the hippocampus and frontal cortex of depressed suicide victims. J Neurochem 1994; 63: 256–265.PubMedCrossRefGoogle Scholar
  33. Greengard P. Phosphorylated proteins as physiological effectors. Science 1978; 199: 146–152.PubMedCrossRefGoogle Scholar
  34. Gu C, Ma YC, Benjamin J, Littman D, Chao MV, Huang XY. Apoptotic signaling through the ß-adrenergic receptor. A new GS effector pathway. J Biol Chem 2000; 275: 20726–20733.PubMedCrossRefGoogle Scholar
  35. Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 2001; 62: 77–91.PubMedCrossRefGoogle Scholar
  36. Hudson CJ, Young LT, Li PP, Warsh JJ. CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia. Synapse 1993; 13: 278–293.PubMedCrossRefGoogle Scholar
  37. Hulley P, Hartikka J, Lubbert H. Cyclic AMP promotes the survival of dopaminergic neurons in vitro and protects them from the toxic effects of MPP+. J Neural Trans (Suppl) 1995; 46: 217–228.Google Scholar
  38. Jensen JB, Shimon H, Morka A. Abnormal phosphorylation in post-mortem brain tissue from bipolar patients. J Neural Transm 2000; 107: 501–509.PubMedCrossRefGoogle Scholar
  39. Jewell-Motz EA, Liggett SB. G protein-coupled receptor kinase specificity for phosphorylation and desensitization of a2-adrenergic receptor subtypes. J Biol Chem 1996; 271: 18082–18087.PubMedCrossRefGoogle Scholar
  40. Jones DJ, Stavinoha WB. Microwave inactivation as a tool for studying the neuropharmacology of cyclic nucleotides. In: G. C. Palmer (ed). Neuropharmacology of Cyclic Nucleotides. Urban & Schwarzenberg, Baltimore: 1979; pp 253–281.Google Scholar
  41. Jordan JD, Landau EM, Iyengar R. Signaling networks: the origins of cellular multitasking. Cell 2000; 103: 193–200.PubMedCrossRefGoogle Scholar
  42. Korswagen HC, Park JH, Ohshima Y, Plasterk RH. An activating mutation in a Caenorhabditis elegans GS protein induces neural degeneration. Genes & Development 1997; 11: 1493–503.CrossRefGoogle Scholar
  43. Li PP, Young LT, Tam YK, Sibony D, Warsh JJ. Effects of chronic lithium and carbamazepine treatment on G-protein subunit expression in rat cerebral cortex. Biol Psychiatry 1993; 34: 162–170.PubMedCrossRefGoogle Scholar
  44. Li PP, Andreopoulos A, Warsh JJ. Signal transduction abnormalities in bipolar affective disorder. In: M. E. A. Reith (ed). Cerebral Signal Transduction: From First to Fourth Messengers. Humana Press, Totowa: 2000; pp 283–309.CrossRefGoogle Scholar
  45. Li X, Greenwood AF, Powers R, Jope RS. Effects of postmortem interval, age, and Alzheimer’s disease on G-proteins in human brain. Neurobiol. Aging 1996; 17: 115–122.PubMedCrossRefGoogle Scholar
  46. Lowther S, Crompton MR, Katona CL, Horton RW. GTPyS and forskolin-stimulated adenylyl cyclase activity in post-mortem brain from depressed suicides and controls. Mol Psychiatry 1996; 1: 470–477.PubMedGoogle Scholar
  47. Lykouras E, Varsou E, Garelis E, Stefanis CN, Malliaras D. Plasma cyclic cAMP in manic-depressive illness. Acta Psychiat. Scand. 1978; 57: 447–453.Google Scholar
  48. Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry 2000a; 48: 740–754.PubMedCrossRefGoogle Scholar
  49. Manji HK, Moore GJ, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry 2000b; 5: 578–593.PubMedCrossRefGoogle Scholar
  50. Mann JJ. Role of the serotonergic system in the pathogenesis of major depression and sdicidal behavior. Neuropsychopharmacology 1999;2 Suppl: 99S–105S.Google Scholar
  51. Meana JJ, Barturen F, Garcia-Sevilla JA. a-Adrenoceptors in the brain of suicide victims: increased receptor density associated with major depression. Biol Psychiatry 1992; 31: 471–490.PubMedCrossRefGoogle Scholar
  52. Milligan G, Unson CG, Wakelam JO. Cholera toxin treatment produces down-regulation of the a-subunit of the stimulatory guanine-nucleotide-binding protein (Gs). Biochem J 1989; 262: 643–649.PubMedGoogle Scholar
  53. Milligan G, Wakelam M. G proteins: Signal Transduction and Disease.; London, Academic Press, 1992.Google Scholar
  54. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, Manji HK. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 2000; 48: 1–8.PubMedCrossRefGoogle Scholar
  55. Morris A.1, Malbon CC. Physiological regulation of G protein-linked signaling. Physiol Rev 1999; 79: 1373–1430.PubMedGoogle Scholar
  56. Nakao N. An increase in intracellular levels of cyclic AMP produces trophic effects on striatal neurons developing in culture. Neuroscience 1998; 82: 1009–1020.PubMedCrossRefGoogle Scholar
  57. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 1998; 95: 13290–13295.PubMedCrossRefGoogle Scholar
  58. Ordway GA, Widdowson PS, Smith KS, Halaris A. Agonist binding to a2-adrenoceptors is elevated in the locus coeruleus from victims of suicide. J Neurochem 1994; 63: 617–624.PubMedCrossRefGoogle Scholar
  59. Often AD, McKnight GS. Overexpression of the type II regulatory subunit of the cAMPdependent protein kinase eliminates the type I holoenzyme in mouse cells. J Biol Chem 1989; 264: 20255–20260.Google Scholar
  60. Ozawa H, Gsell W, Frolich L, Zochling R, Pantucek F, Beckmann H, Riederer P. Imbalance of the Gs and Gib function in post-mortem human brain of depressed patients. J Neural Trans 1993; 94: 63–69.CrossRefGoogle Scholar
  61. 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: 37–45.PubMedCrossRefGoogle Scholar
  62. Pandey GN, Dysken MW, Garver DL, Davis JM. Beta-adrenergic receptor function in affective illness. Am J Psychiatry 1979; 136: 675–678.PubMedGoogle Scholar
  63. Rahman S, Li PP, Young LT, Kofman O, Kish SJ, Warsh JJ. Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder. J Neurochem 1997; 68: 297–304.PubMedCrossRefGoogle Scholar
  64. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 2000; 48: 766–777.PubMedCrossRefGoogle Scholar
  65. Ram A, Guedj F, Cravchik A, Weinstein L, Cao Q, Badner JA, Goldin LR, Grisaru N, Manji HK, Belmaker RH, Gershon ES, Gejman PV. No abnormality in the gene for the G protein stimulatory a subunit in patients with bipolar disorder. Arch Gen Psychiatry 1997; 54: 44–48.PubMedCrossRefGoogle Scholar
  66. Reiach JS, Li PP, Warsh JJ, Kish SJ, Young LT. Reduced adenylyl cyclase immunolabeling and activity in postmortem temporal cortex of depressed suicide victims. J Affective Disorders 1999; 56: 141–151.CrossRefGoogle Scholar
  67. Seifert R, Wenzel-Seifert K, Lee TW, Gether U, Sanders-Bush E, Kobilka BK. Different effects of Gsa splice variants on ß2-adrenoreceptor-mediated signaling. The beta2-adrenoreceptor coupled to the long splice variant of Gsa has properties of a constitutively active receptor. J Biol Chem 1998; 273: 5109–16.CrossRefGoogle Scholar
  68. Sheline YI. 3-D MRI studies of neuroanatomic changes in unipolar major depression: The role of stress and medical comorbidity. Biol Psychiatry 2000; 48: 791–800.Google Scholar
  69. Soares JC, Mann JJ. The anatomy of mood disorders - review of structural neuroimaging studies. Biol Psychiatry 1997; 41: 86–106.PubMedCrossRefGoogle Scholar
  70. Spaulding SW. The ways in which hormones change cyclic adenosine 3’,5’-monophosphatedependent protein kinase subunits, and how such changes affect cell behavior. Endocr Rev 1993; 14: 632–50.PubMedGoogle Scholar
  71. Stoll AL, Renshaw PF, Yurgelun-Todd DA, Cohen BM. Neuroimaging in bipolar disorder: what have we learned? Biol Psychiatry 2000; 48: 505–517.PubMedCrossRefGoogle Scholar
  72. Sutherland EW, Rall TW. Fractionation and characterization of a cyclic adenonsine ribonucleotide formed by tissue particles. J Biol Chem 1958; 232: 1077–1091.PubMedGoogle Scholar
  73. Toyoshige M, Okuya S, Rebois V. Choleragen catalyzes ADP-ribosylation of the stimulatory G protein heterotrimer but not its free a-subunit. Biochemistry 1994; 33: 4865–4871.PubMedCrossRefGoogle Scholar
  74. Tsai G, Coyle JT. N-acetylaspartate in neuropsychiatric disorders. Prog in Neurobiol 1995; 46: 531–540.CrossRefGoogle Scholar
  75. Walseth TF, Zhang HJ, Olson LK, Schroeder WA, Robertson RP. Increase in Gs and cyclic AMP generation in HIT cells. Evidence that the 45-kDa a-subunit of Gs has greater functional activity than the 52-kDa a-subunit. J Biol Chem 1989; 264: 21106–21111.PubMedGoogle Scholar
  76. Walton MR, Dragunow I. Is CREB a key to neuronal survival? Trends Neurosci 2000; 23: 48–53.PubMedCrossRefGoogle Scholar
  77. Wang JF, Young LT, Li PP, Warsh JJ. Signal transduction abnormalities in bipolar disorder. In: L. T. Young and R. T. Joffe (eds). Bipolar Disorder: Biological Models and Their Clinical Application. Marcel-Dekker Inc., New York; 1997; pp 41–79.Google Scholar
  78. Warsh JJ, Chiu AS, Li PP. Noradrenergic mechanisms in affective disorders: contributions on receptor research. In: A. K. Sen and T. Lee (eds). Receptors and Ligands in Psychiatry and Neurology. Cambridge University Press, Cambridge; 1988; pp 271–302.Google Scholar
  79. Warsh JJ, Li PP. Second messenger systems and mood disorders. Curr Opin Psychiatry 1996; 9: 23–29.CrossRefGoogle Scholar
  80. Warsh JJ, Li PP. Postmortem Brain Studies in Bipolar Disorder. In: J. C. Soares and S. Gershon (eds). Bipolar Disorders: Basic Mechanisms and Therapeutic Implications. Marcel Dekker, Inc., New York; 2000; pp 201–226.Google Scholar
  81. Warsh JJ, Young LT, Li PP. Guanine nucleotide binding (G) protein disturbances in bipolar affective disorder. In: H. K. Manji, C. Bowden and R. H. Belmaker (eds). Mechanisms of Action of Antibipolar Drugs: Focus on lithium, carbamazepine and valproic acid. American Psychiatric Association Press, Inc., Washington; 2000; pp 299–319.Google Scholar
  82. Winsberg ME, Sachs N, Tate DL, Adalsteinsson E, Spielman D, Ketter TA. Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biol Psychiatry 2000; 47: 475–481.PubMedCrossRefGoogle Scholar
  83. Yamamoto KK, Gonzalez GA, Biggs WH, 3rd, Montminy MR. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature 1988; 334: 494–498.PubMedCrossRefGoogle Scholar
  84. Yamashita N, Hayashi A, Baba J, Sawa A. Rolipram, a phosphodiesterase-4-selective inhibitor, promotes the survival of cultured rat dopaminergic neurons. Jap J Pharmacol 1997; 75: 155–159.PubMedCrossRefGoogle Scholar
  85. Yan L, Herrmann V, Hofer JK, Insel PA. Beta-adrenergic receptor/cAMP-mediated signaling and apoptosis of S49 lymphoma cells. Am J Physiol - Cell Physiol 2000; 279: C1665–1674.PubMedGoogle Scholar
  86. Young LT, Li PP, Kish SJ, Siu KP, Warsh JJ. Postmortem cerebral cortex Gs alpha-subunit levels are elevated in bipolar affective disorder. Brain Res 1991a; 553: 323–326.PubMedCrossRefGoogle Scholar
  87. Young LT, Warsh JJ, Li PP, Siu KP, Becker L, Gilbert J, Hornykiewicz O, Kish SJ. Maturational and aging effects on guanine nucleotide binding protein immunoreactivity in human brain. Brain Res. Dev Brain Res 1991b; 61: 243–248.PubMedCrossRefGoogle Scholar
  88. Young LT, Li PP, Kish SJ, Siu KP, Kamble A, Hornykiewicz O, Warsh JJ. Cerebral cortex Gsa protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem 1993; 6: 890–898.CrossRefGoogle Scholar
  89. Young LT, Li PP, Kish SJ, Warsh JJ. Cerebral cortex ß-adrenoceptor binding in bipolar affective disorder. J Affect Disord 1994; 30: 89–92.PubMedCrossRefGoogle Scholar
  90. Young LT, Asghari V, Li PP, Kish SJ, Fahnestock M, Warsh JJ. Stimulatory G-protein a-subunit mRNA levels are not increased in autopsied cerebral cortex from patients with bipolar disorder. Brain Res Mol Brain Res 1996; 42: 45–50.PubMedCrossRefGoogle Scholar
  91. Zhu LP, Yu XD, Ling S, Brown RA, Kuo TH. Mitochondrial Cat+ homeostasis in the regulation of apoptotic and necrotic cell deaths. Cell Calcium 2000; 28: 107–117.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Annisa Chang
  • Peter P. Li
  • Jerry J. Warsh

There are no affiliations available

Personalised recommendations