Lithium (Li) is the main mood stabilizer and acts on multiple biochemical targets, leading to neuronal plasticity. Several clinical studies have shown that tamoxifen (TMX) – a protein kinase C (PKC) inhibitor – has been effective in treating acute mania. The present study aims to evaluate the effects of TMX on biochemical targets of Li, such as glycogen synthase kinase-3β (GSK-3β), PKC, PKA, CREB, BDNF and NGF, in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were treated with d-AMPH (2mg/kg, once a day) or saline (Sal; NaCl 0.9%, w/v), Li (47.5 mg/kg, intraperitoneally (i.p.), twice a day) or TMX (1 mg/kg i.p., twice a day) or Sal in protocols of reversion and prevention treatment. Locomotor behavior was assessed using the open-field task, and protein levels were measured by immunoblot. Li and TMX reversed and prevented d-AMPH-induced hyperactivity. Western blot showed that d-AMPH significantly increased GSK-3 and PKC levels, and decreased pGSK-3, PKA, NGF, BDNF and CREB levels in the structures analyzed. Li and TMX were able to prevent and reverse these changes induced by d-AMPH in most structures evaluated. The present study demonstrated that the PKC inhibitor modulates the alterations in the behavior, neurotrophic and apoptosis pathway induced by d-AMPH, reinforcing the need for more studies of PKC as a possible target for treatment of bipolar disorder.
AmrollahiZRezaeiFSalehiB. (2011) 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 Disord129: 327–331.
BoudanovaENavaroliDMMelikianHE (2008) Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent. Neuropharmacology54: 605–612.
4.
BradfordMM. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem72: 248–254.
5.
ChenRFurmanCAZhangM. (2009) Protein kinase Cbeta is a critical regulator of dopamine transporter trafficking and regulates the behavioral response to amphetamine in mice. J Pharmacol Exp Ther328: 912–920.
6.
ChiuCTChuangDM (2010) Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther128: 281–304.
7.
da-RosaDDValvassoriSSSteckertAV. (2012) Effects of lithium and valproate on oxidative stress and behavioral changes induced by administration of m-AMPH. Psychiatry Res, in press.
8.
DavisLLBartolucciAPettyF (2005) Divalproex in the treatment of bipolar depression: A placebo-controlled study. J Affect Disord85: 259–266.
9.
De SouzaCTGasparettiALPereira-da-SilvaM. (2003) Peroxisome proliferator-activated receptor gamma coactivator-1-dependent uncoupling protein-2 expression in pancreatic islets of rats: A novel pathway for neural control of insulin secretion. Diabetologia46: 1522–1531.
10.
DiazGranadosNZarateCA (2008) A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr Psychiatry Rep10: 510–519.
11.
EinatHManjiHK (2006) Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Biol Psychiatry59: 1160–1171.
12.
EinatHYuanPGouldTD. (2003) The role of the extracellular signal-regulated kinase signaling pathway in mood regulation. J Neurosci23: 7311–7316.
13.
EinatHYuanPSzaboST. (2007) Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: Implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology55: 123–131.
14.
FreyBNAndreazzaACCeresérKM. (2006a) Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci79: 281–286.
15.
FreyBNAndreazzaACRosaAR. (2006b) Lithium increases nerve growth factor levels in the rat hippocampus in an animal model of mania. Behav Pharmacol17: 311–318.
16.
GouldTJKeithRABhatRV (2001) Differential sensitivity to lithium's reversal of amphetamine-induced open-field activity in two inbred strains of mice. Behav Brain Res118: 95–105.
17.
GouldTDQuirozJASinghJ. (2004) Emerging experimental therapeutics for bipolar disorder: Insights from the molecular and cellular actions of current mood stabilizers. Mol Psychiatry9: 734–755.
18.
GrimesCAJopeRS (2001) CREB DNA binding activity is inhibited by glycogen synthase kinase-3β and facilitated by lithium. J Neurochem78: 1219–1232.
19.
HashimotoRTakeiNShimazuK. (2002) Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology43: 1173–1179.
20.
HellwegRLangUENagelM. (2002) Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats. Mol Psychiatry7: 604–608.
21.
HoneckerHCoperH (1975) Kinetics and metabolism of amphetamine in the brain of rats of different ages. Naunyn Schmiedebergs Arch Pharmacol291: 111–121.
22.
JohnsonLAGuptaroyBLundD. (2005) Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta. J Biol Chem280: 10914–10919.
23.
KeckPEManjiHK (2002) Current and Emerging Treatments for Acute Mania and Long-Term Prophylaxis for Bipolar Disorder. Philadelphia: Lippincott Williams & Wilkins.
24.
LaemmliUK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature227: 680–685.
25.
LaiYLRodarteJRHyattRE (1977) Effect of body position on lung emptying in recumbent anesthetized dogs. J Appl Physiol43: 983–987.
26.
LallemendFHadjabSHansG. (2005) Activation of protein kinase C beta I constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons. J Cell Sci118: 4511–4525.
27.
LiXJopeRS (2010) Is glycogen synthase kinase-3 a central modulator in mood regulation?Neuropsychopharmacology35: 2143–2154.
28.
Machado-VieiraRKapczinskiFSoaresJC (2004) Perspectives for the development of animal models of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry28: 209–224.
29.
ManjiHKChenG (2002) PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers. Mol Psychiatry7 (Suppl. 1): S46–S56.
30.
ManjiHKLenoxRH. (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 Psychiatry46: 1328–1351.
31.
MorettiMValvassoriSSSteckertAV. (2011) Tamoxifen effects on respiratory chain complexes and creatine kinase activities in an animal model of mania. Pharmacol Biochem Behav98: 304–310.
32.
NagahiroSTakadaADiksicM. (1990) A new method to measure brain serotonin synthesis in vivo. II. A practical autoradiographic method tested in normal and lithium-treated rats. J Cereb Blood Flow Metab10: 13–21.
33.
NishizukaY (1992) Membrane phospholipid degradation and protein kinase C for cell signaling. Neurosci Res15: 3–5.
34.
RankinSLGuyCSRahimtulaM. (2008) Neurotrophin-induced upregulation of p75NTR via a protein kinase C-delta-dependent mechanism. Brain Res1217: 10–24.
35.
SaarelainenTHendolinPLucasG. (2003) Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci23: 349–357.
36.
SabioniPBarettaIPNinomiyaEM. (2008) The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC inhibiting and antiestrogenic drugs. Prog Neuropsychopharmacol Biol Psychiatry32: 1927–1931.
37.
SairanenMLucasGErnforsP. (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci25: 1089–1094.
38.
SimsDE (1991) Recent advances in pericyte biology implications for health and disease. Can J Cardiol7: 431–443.
39.
SonnewaldUHertzLSchousboeA (1998) Mitochondrial heterogeneity in the brain at the cellular level. J Cereb Blood Flow Metab18: 231–237.
40.
SteckertAVValvassoriSSMinaF. (2012) Protein kinase C and oxidative stress in an animal model of mania. Curr Neurovasc Res9: 47–57.
41.
StrakowskiSMDelBelloMPAdlerC. (2000) Neuroimaging in bipolar disorder. Bipolar Disord2: 148–164.
42.
StrakowskiSMDelbelloMPAdlerCM (2005) The functional neuroanatomy of bipolar disorder: A review of neuroimaging findings. Mol Psychiatry10: 105–116.
43.
SulzerDRayportS (1990) Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: A mechanism of action. Neuron5: 797–808.
44.
ViwatpinyoKChongthammakunS (2009) Activation of group I metabotropic glutamate receptors leads to brain-derived neurotrophic factor expression in rat C6 cells. Neurosci Lett467: 127–130.
45.
WronaMZYangZZhangF. (1997) Potential new insights into the molecular mechanisms of methamphetamine-induced neurodegeneration. NIDA Res Monogr173: 146–174.
46.
XuCMWangJWuP. (2011) Glycogen synthase kinase 3β in the nucleus accumbens core is critical for methamphetamine-induced behavioral sensitization. J Neurochem118: 126–139.
47.
YildizAGuleryuzSAnkerstDP. (2008) Protein kinase C inhibition in the treatment of mania: A double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry65: 255–263.
48.
YildizAVietaELeuchtS. (2011) Efficacy of antimanic treatments: Meta-analysis of randomized, controlled trials. Neuropsychopharmacology36: 375–389.
49.
ZarateCASinghJBCarlsonPJ. (2007) Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord9: 561–570
50.
ZarateCASinghJManjiHK (2006) Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry59: 1006–1020.
51.
ZirrgiebelUOhgaYCarterB. (1995) Characterization of TrkB receptor-mediated signaling pathways in rat cerebellar granule neurons: Involvement of protein kinase C in neuronal survival. J Neurochem65: 2241–2250.
