Molecular Neurobiology

, Volume 44, Issue 3, pp 407–419 | Cite as

A Role for the PKC Signaling System in the Pathophysiology and Treatment of Mood Disorders: Involvement of a Functional Imbalance?

  • Erika Abrial
  • Guillaume Lucas
  • Hélène Scarna
  • Nasser Haddjeri
  • Laura Lambás-Señas


Mood disorders, such as bipolar and major depressive disorders, are frequent, severe, and often disabling neuropsychiatric diseases affecting millions of individuals worldwide. Available mood stabilizers and antidepressants remain unsatisfactory because of their delayed and partial therapeutic efficacy. Therefore, the development of targeted therapies, working more rapidly and being fully effective, is urgently needed. In this context, the protein kinase C (PKC) signaling system, which regulates multiple neuronal processes implicated in mood regulation, can constitute a novel therapeutic target. This paper reviews the currently available knowledge regarding the role of the PKC signaling pathway in the pathophysiology of mood disorders and the therapeutic potential of PKC modulators. Current antidepressants and mood stabilizers have been shown to modulate the PKC pathway, and the inhibition of this intracellular signaling cascade results in antimanic-like properties in animal models. Disrupted PKC activity has been found both in postmortem brains and platelet from patients with mood disorders. Finally, the PKC inhibitor tamoxifen has recently demonstrated potent antimanic properties in several clinical trials. Overall, emerging data from preclinical and clinical research suggest an imbalance of the PKC signaling system in mood disorders. Thus, PKC may be a critical molecular target for the development of innovative therapeutics.


Depression Mania Protein kinase C Mood disorders Intracellular signaling pathways 


  1. 1.
    Kessler RC, Chiu WT, Demler O, Walters EE (2005) Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:617–627. doi: 10.1001/archpsyc.62.6.617 PubMedGoogle Scholar
  2. 2.
    American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (Revised 4th edn). American Psychiatric Association, Washington, DCGoogle Scholar
  3. 3.
    Frye MA (2011) Clinical practice. Bipolar disorder–a focus on depression. N Engl J Med 364:51–59. doi: 10.1056/NEJMcp1000402 PubMedGoogle Scholar
  4. 4.
    Blier P, de Montigny C (1999) Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology 21:91S–98S. doi: 10.1016/S0893-133X(99)00036-6 PubMedGoogle Scholar
  5. 5.
    Faure C, Mnie-Filali O, Haddjeri N (2006) Long-term adaptive changes induced by serotonergic antidepressant drugs. Expert Rev Neurother 6:235–245. doi: 10.1586/14737175.6.2.235 PubMedGoogle Scholar
  6. 6.
    Chen J, Fang Y, Kemp DE et al (2010) Switching to hypomania and mania: differential neurochemical, neuropsychological, and pharmacologic triggers and their mechanisms. Curr Psychiatry Rep 12:512–521. doi: 10.1007/s11920-010-0157-z PubMedGoogle Scholar
  7. 7.
    Rapoport SI, Basselin M, Kim H-W, Rao JS (2009) Bipolar disorder and mechanisms of action of mood stabilizers. Brain Res Rev 61:185–209. doi: 10.1016/j.brainresrev.2009.06.003 PubMedGoogle Scholar
  8. 8.
    Zarate C, Machado-Vieira R, Henter I et al (2010) Glutamatergic modulators: the future of treating mood disorders? Harv Rev Psychiatry 18:293–303. doi: 10.3109/10673229.2010.511059 PubMedGoogle Scholar
  9. 9.
    Castrén E (2005) Is mood chemistry? Nat Rev Neurosci 6:241–246. doi: 10.1sj.npp./nrn1629 PubMedGoogle Scholar
  10. 10.
    Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33:88–109. doi: 10.1sj.npp./sj.npp.1301574 PubMedGoogle Scholar
  11. 11.
    Drevets WC (2001) Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 11:240–249. doi: 10.1016/S0959-4388(00)00203-8 PubMedGoogle Scholar
  12. 12.
    Artigas F, Nutt DJ, Shelton R (2002) Mechanism of action of antidepressants. Psychopharmacol Bull 36(Suppl 2):123–132PubMedGoogle Scholar
  13. 13.
    Tanis KQ, Duman RS (2007) Intracellular signaling pathways pave roads to recovery for mood disorders. Ann Med 39:531–544. doi: 10.1080/07853890701483270 PubMedGoogle Scholar
  14. 14.
    Ohno S, Nishizuka Y (2002) Protein kinase C isotypes and their specific functions: prologue. J Biochem 132:509–511PubMedGoogle Scholar
  15. 15.
    Wetsel WC, Khan WA, Merchenthaler I et al (1992) Tissue and cellular distribution of the extended family of protein kinase C isoenzymes. J Cell Biol 117:121–133PubMedGoogle Scholar
  16. 16.
    Naik MU, Benedikz E, Hernandez I et al (2000) Distribution of protein kinase Mzeta and the complete protein kinase C isoform family in rat brain. J Comp Neurol 426:243–258PubMedGoogle Scholar
  17. 17.
    Tanaka C, Saito N (1992) Localization of subspecies of protein kinase C in the mammalian central nervous system. Neurochem Int 21:499–512PubMedGoogle Scholar
  18. 18.
    Amadio M, Battaini F, Pascale A (2006) The different facets of protein kinases C: old and new players in neuronal signal transduction pathways. Pharmacol Res 54:317–325. doi: 10.1016/j.phrs.2006.08.002 PubMedGoogle Scholar
  19. 19.
    Boehm J, Kang M-G, Johnson RC et al (2006) Synaptic Incorporation of AMPA Receptors during LTP Is Controlled by a PKC Phosphorylation Site on GluR1. Neuron 51:213–225. doi: 10.1016/j.neuron.2006.06.013 PubMedGoogle Scholar
  20. 20.
    Dai S, Hall DD, Hell JW (2009) Supramolecular assemblies and localized regulation of voltage-gated ion channels. Physiol Rev 89:411–452. doi: 10.1152/physrev.00029.2007 PubMedGoogle Scholar
  21. 21.
    Goode N, Hughes K, Woodgett JR, Parker PJ (1992) Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes. J Biol Chem 267:16878–16882PubMedGoogle Scholar
  22. 22.
    Huang K-P (1989) The mechanism of protein kinase C activation. Trends Neurosci 12:425–432. doi: 10.1016/0166-2236(89)90091-X PubMedGoogle Scholar
  23. 23.
    Jayanthi LD, Samuvel DJ, Blakely RD, Ramamoorthy S (2005) Evidence for biphasic effects of protein kinase C on serotonin transporter function, endocytosis, and phosphorylation. Mol Pharmacol 67:2077–2087. doi: 10.1124/mol.104.009555 PubMedGoogle Scholar
  24. 24.
    Kolch W, Heidecker G, Kochs G et al (1993) Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 364:249–252. doi: 10.1sj.npp./364249a0 PubMedGoogle Scholar
  25. 25.
    Martelli AM, Evangelisti C, Nyakern M, Manzoli FA (2006) Nuclear protein kinase C. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1761:542–551. doi: 10.1016/j.bbalip.2006.02.009 Google Scholar
  26. 26.
    Morgan A, Burgoyne RD, Barclay JW et al (2005) Regulation of exocytosis by protein kinase C. Biochem Soc Trans 33:1341–1344. doi: 10.1042/BST20051341 PubMedGoogle Scholar
  27. 27.
    Pasinelli P, Ramakers GM, Urban IJ et al (1995) Long-term potentiation and synaptic protein phosphorylation. Behav Brain Res 66:53–59PubMedGoogle Scholar
  28. 28.
    Yoshimasa T, Sibley DR, Bouvier M et al (1987) Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation. Nature 327:67–70. doi: 10.1sj.npp./327067a0 PubMedGoogle Scholar
  29. 29.
    Hofmann J (1997) The potential for isoenzyme-selective modulation of protein kinase C. FASEB J 11:649–669PubMedGoogle Scholar
  30. 30.
    Nelson TJ, Alkon DL (2009) Neuroprotective versus tumorigenic protein kinase C activators. Trends Biochem Sci 34:136–145. doi: 10.1016/j.tibs.2008.11.006 PubMedGoogle Scholar
  31. 31.
    Ron D, Kazanietz MG (1999) New insights into the regulation of protein kinase C and novel phorbol ester receptors. FASEB J 13:1658–1676PubMedGoogle Scholar
  32. 32.
    Bitran JA, Manji HK, Potter WZ, Gusovsky F (1995) Down-regulation of PKC alpha by lithium in vitro. Psychopharmacol Bull 31:449–452PubMedGoogle Scholar
  33. 33.
    Manji HK, Lenox RH (1999) Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry 46:1328–1351PubMedGoogle Scholar
  34. 34.
    Manji HK, Etcheberrigaray R, Chen G, Olds JL (1993) Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme. J Neurochem 61:2303–2310PubMedGoogle Scholar
  35. 35.
    Jensen JB, Mørk A (1997) Altered protein phosphorylation in the rat brain following chronic lithium and carbamazepine treatments. Eur Neuropsychopharmacol 7:173–179PubMedGoogle Scholar
  36. 36.
    Lenox RH, Watson DG, Patel J, Ellis J (1992) Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 570:333–340PubMedGoogle Scholar
  37. 37.
    Szabo ST, Machado-Vieira R, Yuan P et al (2009) Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology 56:47–55. doi: 10.1016/j.neuropharm.2008.08.015 PubMedGoogle Scholar
  38. 38.
    Chen G, Manji HK, Hawver DB et al (1994) Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem 63:2361–2364PubMedGoogle Scholar
  39. 39.
    Basta-Kaim A, Budziszewska B, Jaworska-Feil L et al (2006) Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. Neuropsychopharmacology 31:853–865. doi: 10.1038/sj.npp.1300911 PubMedGoogle Scholar
  40. 40.
    Moore GJ, Bebchuk JM, Parrish JK et al (1999) Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. Am J Psychiatry 156:1902–1908PubMedGoogle Scholar
  41. 41.
    Mann CD, Vu TB, Hrdina PD (1995) Protein kinase C in rat brain cortex and hippocampus: effect of repeated administration of fluoxetine and desipramine. Br J Pharmacol 115:595–600PubMedGoogle Scholar
  42. 42.
    Rausch JL, Gillespie CF, Fei Y et al (2002) Antidepressant effects on kinase gene expression patterns in rat brain. Neurosci Lett 334:91–94PubMedGoogle Scholar
  43. 43.
    Kim SH, Kim MK, Yu HS et al (2010) Electroconvulsive seizure increases phosphorylation of PKC substrates, including GAP-43, MARCKS, and neurogranin, in rat brain. Prog Neuropsychopharmacol Biol Psychiatry 34:115–121. doi: 10.1016/j.pnpbp. 2009.10.009 PubMedGoogle Scholar
  44. 44.
    Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169. doi: 10.1sj.npp./nn.2647 PubMedGoogle Scholar
  45. 45.
    Frey BN, Valvassori SS, Réus GZ et al (2006) Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci 31:326–332PubMedGoogle Scholar
  46. 46.
    Wesołowska A, Partyka A, Jastrzębska-Więsek M et al (2010) Tail suspension test does not detect antidepressant-like properties of atypical antipsychotics. Behav Pharmacol. doi: 10.1097/FBP.0b013e3283423d6b
  47. 47.
    Abrial E, Etievant A, Bétry C et al (2011) Manic-like response to amphetamine or sleep deprivation in rats is decreased by protein kinase C inhibition. 10th Meeting of Société des Neurosciences, Marseille, France, May 24–27, 2011Google Scholar
  48. 48.
    Einat H, Yuan P, Szabo ST et al (2007) Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology 55:123–131. doi: 10.1159/000106054 PubMedGoogle Scholar
  49. 49.
    Sabioni P, Baretta IP, Ninomiya EM et al (2008) The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC-inhibiting and antiestrogenic drugs. Prog Neuropsychopharmacol Biol Psychiatry 32:1927–1931. doi: 10.1016/j.pnpbp.2008.09.023 PubMedGoogle Scholar
  50. 50.
    Browman KE, Kantor L, Richardson S et al (1998) Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies. Brain Res 814:112–119PubMedGoogle Scholar
  51. 51.
    Steketee JD (1993) Injection of the protein kinase inhibitor H7 into the A10 dopamine region blocks the acute responses to cocaine: behavioral and in vivo microdialysis studies. Neuropharmacology 32:1289–1297PubMedGoogle Scholar
  52. 52.
    Kantor L, Gnegy ME (1998) Protein kinase C inhibitors block amphetamine-mediated dopamine release in rat striatal slices. J Pharmacol Exp Ther 284:592–598PubMedGoogle Scholar
  53. 53.
    Loweth JA, Svoboda R, Austin JD et al (2009) The PKC inhibitor Ro31-8220 blocks acute amphetamine-induced dopamine overflow in the nucleus accumbens. Neurosci Lett 455:88–92. doi: 10.1016/j.neulet.2009.03.012 PubMedGoogle Scholar
  54. 54.
    Chen R, Furman CA, Zhang M et al (2009) Protein kinase Cbeta is a critical regulator of dopamine transporter trafficking and regulates the behavioral response to amphetamine in mice. J Pharmacol Exp Ther 328:912–920. doi: 10.1124/jpet.108.147959 PubMedGoogle Scholar
  55. 55.
    Gessa GL, Pani L, Fadda P, Fratta W (1995) Sleep deprivation in the rat: an animal model of mania. Eur Neuropsychopharmacol 5(Suppl):89–93PubMedGoogle Scholar
  56. 56.
    Einat H, Manji HK (2006) Cellular Plasticity Cascades: Genes-To-Behavior Pathways in Animal Models of Bipolar Disorder. Biol Psychiatry 59:1160–1171. doi: 10.1016/j.biopsych.2005.11.004 PubMedGoogle Scholar
  57. 57.
    Cervo L, Mukherjee S, Bertaglia A, Samanin R (1997) Protein kinases A and C are involved in the mechanisms underlying consolidation of cocaine place conditioning. Brain Res 775:30–36PubMedGoogle Scholar
  58. 58.
    Lai Y-T, Fan H-Y, Cherng CG et al (2008) Activation of amygdaloid PKC pathway is necessary for conditioned cues-provoked cocaine memory performance. Neurobiol Learn Mem 90:164–170. doi: 10.1016/j.nlm.2008.03.006 PubMedGoogle Scholar
  59. 59.
    Narita M, Akai H, Nagumo Y et al (2004) Implications of protein kinase C in the nucleus accumbens in the development of sensitization to methamphetamine in rats. Neuroscience 127:941–948. doi: 10.1016/j.neuroscience.2004.06.017 PubMedGoogle Scholar
  60. 60.
    Narita M, Aoki T, Ozaki S et al (2001) Involvement of protein kinase Cgamma isoform in morphine-induced reinforcing effects. Neuroscience 103:309–314PubMedGoogle Scholar
  61. 61.
    Olive MF, Mehmert KK, Messing RO, Hodge CW (2000) Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCepsilon-deficient mice. Eur J Neurosci 12:4131–4140PubMedGoogle Scholar
  62. 62.
    Abrial E, Haddjeri N, Lambás-Señas L (2010) Effects of protein kinase c inhibitors tamoxifen and chelerythrine on anxiety and depression-like behaviors. FENS Abstr. vol. 5Google Scholar
  63. 63.
    Raygada M, Cho E, Hilakivi-Clarke L (1998) High maternal intake of polyunsaturated fatty acids during pregnancy in mice alters offsprings’ aggressive behavior, immobility in the swim test, locomotor activity and brain protein kinase C activity. J Nutr 128:2505–2511PubMedGoogle Scholar
  64. 64.
    Birnbaum SG, Yuan PX, Wang M et al (2004) Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 306:882–884. doi: 10.1126/science.1100021 PubMedGoogle Scholar
  65. 65.
    Hains AB, Vu MAT, Maciejewski PK et al (2009) Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proc Natl Acad Sci U S A 106:17957–17962. doi: 10.1073/pnas.0908563106 PubMedGoogle Scholar
  66. 66.
    Palumbo ML, Zorrilla Zubilete MA, Cremaschi GA, Genaro AM (2009) Different effect of chronic stress on learning and memory in BALB/c and C57BL/6 inbred mice: Involvement of hippocampal NO production and PKC activity. Stress 12:350–361. doi: 10.1080/10253890802506383 PubMedGoogle Scholar
  67. 67.
    Park S-H, Choi S-H, Lee J et al (2008) Effects of repeated citalopram treatments on chronic mild stress-induced growth associated protein-43 mRNA expression in rat hippocampus. Korean J Physiol Pharmacol 12:117–123. doi: 10.4196/kjpp.2008.12.3.117 PubMedGoogle Scholar
  68. 68.
    Han F, Shioda N, Moriguchi S et al (2008) Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) treatment rescues olfactory bulbectomy-induced memory impairment by activating Ca2+/calmodulin kinase II and protein kinase C in mouse hippocampus. J Pharmacol Exp Ther 326:127–134. doi: 10.1124/jpet.108.137471 PubMedGoogle Scholar
  69. 69.
    Moriguchi S, Han F, Nakagawasai O et al (2006) Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice. J Neurochem 97:22–29. doi: 10.1111/j.1471-4159.2006.03710.x PubMedGoogle Scholar
  70. 70.
    Dwivedi Y, Mondal AC, Rizavi HS et al (2005) Single and repeated stress-induced modulation of phospholipase C catalytic activity and expression: role in LH behavior. Neuropsychopharmacology 30:473–483. doi: 10.1038/sj.npp. 1300605 PubMedGoogle Scholar
  71. 71.
    Wu J, Song T-B, Li Y-J et al (2007) Prenatal restraint stress impairs learning and memory and hippocampal PKCbeta1 expression and translocation in offspring rats. Brain Res 1141:205–213. doi: 10.1016/j.brainres.2007.01.024 PubMedGoogle Scholar
  72. 72.
    Alfonso J, Frick LR, Silberman DM et al (2006) Regulation of Hippocampal Gene Expression Is Conserved in Two Species Subjected to Different Stressors and Antidepressant Treatments. Biol Psychiatry 59:244–251. doi: 10.1016/j.biopsych.2005.06.036 PubMedGoogle Scholar
  73. 73.
    Zheng H, Ma G-yu, Fu X-chun, DU H-guang (2008) Effects of paroxetine on protein kinase PKA, PKC and CaMKII activity in different brain regions in a rat depression model. Nan Fang Yi Ke Da Xue Xue Bao 28:1223–1225Google Scholar
  74. 74.
    Lueptow LM, Zhao Z, O’Donnell JM (2010) Norepinephrine and serotonin transporter regulation is important for antidepressant-like effects on behavior in rats. SFN abstr. 2010Google Scholar
  75. 75.
    Sun M-K, Alkon DL (2005) Dual effects of bryostatin-1 on spatial memory and depression. Eur J Pharmacol 512:43–51. doi: 10.1016/j.ejphar.2005.02.028 PubMedGoogle Scholar
  76. 76.
    Baum AE, Akula N, Cabanero M et al (2008) A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13:197–207. doi: 10.1038/ PubMedGoogle Scholar
  77. 77.
    Burton PR, Clayton DG, Cardon LR (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678. doi:  10.1sj.npp./nature05911 Google Scholar
  78. 78.
    Turecki G, Grof P, Cavazzoni P et al (1998) Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder. Mol Psychiatry 3:534–538PubMedGoogle Scholar
  79. 79.
    Ohnishi T, Yamada K, Ohba H et al (2007) A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology 32:1727–1737. doi: 10.1038/sj.npp.1301307 PubMedGoogle Scholar
  80. 80.
    Sjøholt G, Ebstein RP, Lie RT et al (2004) Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder. Mol Psychiatry 9:621–629. doi: 10.1038/ PubMedGoogle Scholar
  81. 81.
    Pandey GN, Dwivedi Y, Pandey SC et al (1997) Protein kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett 228:111–114PubMedGoogle Scholar
  82. 82.
    Pandey GN, Dwivedi Y, Rizavi HS et al (2004) Decreased catalytic activity and expression of protein kinase C isozymes in teenage suicide victims: a postmortem brain study. Arch Gen Psychiatry 61:685–693. doi: 10.1001/archpsyc.61.7.685 PubMedGoogle Scholar
  83. 83.
    Wang HY, Friedman E (1996) Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry 40:568–575PubMedGoogle Scholar
  84. 84.
    Jope RS, Song L, Li PP et al (1996) The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain. J Neurochem 66:2402–2409PubMedGoogle Scholar
  85. 85.
    Mathews R, Li PP, Young LT et al (1997) Increased G alpha q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder. Biol Psychiatry 41:649–656. doi: 10.1016/S0006-3223(96)00113-8 PubMedGoogle Scholar
  86. 86.
    Shelton RC, Hal Manier D, Lewis DA (2009) Protein kinases A and C in post-mortem prefrontal cortex from persons with major depression and normal controls. Int J Neuropsychopharmacol 12:1223–1232. doi: 10.1017/S1461145709000285 PubMedGoogle Scholar
  87. 87.
    Pandey GN, Dwivedi Y, Ren X et al (2003) Altered expression and phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) in postmortem brain of suicide victims with or without depression. J Psychiatr Res 37:421–432PubMedGoogle Scholar
  88. 88.
    Ohmori S, Sakai N, Shirai Y et al (2000) Importance of protein kinase C targeting for the phosphorylation of its substrate, myristoylated alanine-rich C-kinase substrate. J Biol Chem 275:26449–26457. doi: 10.1074/jbc.M003588200 PubMedGoogle Scholar
  89. 89.
    Wang HY, Markowitz P, Levinson D et al (1999) Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J Psychiatr Res 33:171–179PubMedGoogle Scholar
  90. 90.
    Friedman E, Wang HY, Levinson D et al (1993) Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 33:520–525PubMedGoogle Scholar
  91. 91.
    Hahn C-G, Umapathy C, Wang H-Y et al (2005) Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. J Psychiatr Res 39:355–363PubMedGoogle Scholar
  92. 92.
    Pandey GN, Ren X, Dwivedi Y, Pavuluri MN (2008) Decreased protein kinase C (PKC) in platelets of pediatric bipolar patients: effect of treatment with mood stabilizing drugs. J Psychiatr Res 42:106–116. doi: 10.1016/j.jpsychires.2006.11.004 PubMedGoogle Scholar
  93. 93.
    Young LT, Wang JF, Woods CM, Robb JC (1999) Platelet protein kinase C alpha levels in drug-free and lithium-treated subjects with bipolar disorder. Neuropsychobiology 40:63–66PubMedGoogle Scholar
  94. 94.
    Pandey GN, Dwivedi Y, SridharaRao J et al (2002) Protein kinase C and phospholipase C activity and expression of their specific isozymes is decreased and expression of MARCKS is increased in platelets of bipolar but not in unipolar patients. Neuropsychopharmacology 26:216–228. doi: 10.1016/S0893-133X(01)00327-X PubMedGoogle Scholar
  95. 95.
    Bebchuk JM, Arfken CL, Dolan-Manji S et al (2000) A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch Gen Psychiatry 57:95–97PubMedGoogle Scholar
  96. 96.
    Amrollahi Z, Rezaei F, Salehi B et al (2010) Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J Affect Disord 129:327–331. doi: 10.1016/j.jad.2010.08.015 PubMedGoogle Scholar
  97. 97.
    Kulkarni J, Garland KA, Scaffidi A et al (2006) A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder. Psychoneuroendocrinology 31:543–547. doi: 10.1016/j.psyneuen.2005.11.001 PubMedGoogle Scholar
  98. 98.
    Yildiz A, Guleryuz S, Ankerst DP et al (2008) Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry 65:255–263. doi: 10.1001/archgenpsychiatry.2007.43 PubMedGoogle Scholar
  99. 99.
    Zarate CA, Singh JB, Carlson PJ et al (2007) Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord 9:561–570. doi: 10.1111/j.1399-5618.2007.00530.x PubMedGoogle Scholar
  100. 100.
    Yildiz A, Vieta E, Leucht S, Baldessarini RJ (2011) Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology 36:375–389. doi: 10.1038/npp.2010.192 PubMedGoogle Scholar
  101. 101.
    Saraiva L, Fresco P, Pinto E, Gonçalves J (2003) Isoform-selectivity of PKC inhibitors acting at the regulatory and catalytic domain of mammalian PKC-alpha, -betaI, -delta, -eta and -zeta. J Enzyme Inhib Med Chem 18:475–483. doi: 10.1080/14756360310001603158 PubMedGoogle Scholar
  102. 102.
    Mallinger AG, Thase ME, Haskett R et al (2008) Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms. Bipolar Disord 10:856–866. doi: 10.1111/j.1399-5618.2008.00636.x PubMedGoogle Scholar
  103. 103.
    Schou M (1976) Pharmacology and toxicology of lithium. Annu Rev Pharmacol Toxicol 16:231–243. doi: 10.1146/ PubMedGoogle Scholar
  104. 104.
    Tang P, Roldan G, Brasher PMA et al (2006) A phase II study of carboplatin and chronic high-dose tamoxifen in patients with recurrent malignant glioma. J Neurooncol 78:311–316. doi: 10.1007/s11060-005-9104-y PubMedGoogle Scholar
  105. 105.
    Thompson DS, Spanier CA, Vogel VG (1999) The Relationship Between Tamoxifen, Estrogen, and Depressive Symptoms. Breast J 5:375–382PubMedGoogle Scholar
  106. 106.
    Nelson TJ, Cui C, Luo Y, Alkon DL (2009) Reduction of beta-amyloid levels by novel protein kinase C(epsilon) activators. J Biol Chem 284:34514–34521. doi: 10.1074/jbc.M109.016683 PubMedGoogle Scholar
  107. 107.
    Pacheco MA, Stockmeier C, Meltzer HY et al (1996) Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain. Brain Res 723:37–45PubMedGoogle Scholar
  108. 108.
    Coull MA, Lowther S, Katona CL, Horton RW (2000) Altered brain protein kinase C in depression: a post-mortem study. Eur Neuropsychopharmacol 10:283–288PubMedGoogle Scholar
  109. 109.
    Hrdina P, Faludi G, Li Q et al (1998) Growth-associated protein (GAP-43), its mRNA, and protein kinase C (PKC) isoenzymes in brain regions of depressed suicides. Mol Psychiatry 3:411–418PubMedGoogle Scholar
  110. 110.
    Soares JC, Chen G, Dippold CS et al (2000) Concurrent measures of protein kinase C and phosphoinositides in lithium-treated bipolar patients and healthy individuals: a preliminary study. Psychiatry Res 95:109–118PubMedGoogle Scholar
  111. 111.
    Pandey GN, Dwivedi Y, Kumari R, Janicak PG (1998) Protein kinase C in platelets of depressed patients. Biol Psychiatry 44:909–911PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Laboratoire de NeuropsychopharmacologieUniversité Lyon 1Lyon Cedex 08France
  2. 2.INSERMParis Cedex 13France

Personalised recommendations