Rationale: In the context of bipolar disorder (BPD) research it was demonstrated that administration of the structurally dissimilar mood stabilizers lithium and valproate produced a striking reduction in protein kinase C (PKC) in rat brain. In a small clinical study, tamoxifen (a PKC inhibitor) had antimanic efficacy. However, both lithium and valproate exert many biochemical changes and attribution of therapeutic relevance to any molecular findings needs to be based on linking them to behavioral effects. Objectives: The present study was designed to explore such relationship by studying the effects of PKC inhibition in amphetamine-induced behavioral animal models of mania and changes in GAP-43. Methods: The effects of two daily tamoxifen (1 mg/kg) i.p. injections on acute or chronic (7 injections) amphetamine (0.5 mg/kg) -induced behaviors and GAP-43 phosphorylation were tested. Results: The study demonstrates that tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity levels and normalized amphetamine-induced increase in visits to the center of an open field (representing risk-taking behavior). Tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43, a result that is consistent with the behavioral findings. Conclusions: These results support the possibility that PKC signaling may play an important role in the pathophysiology and treatment of BPD. These findings may have direct clinical implications as they offer a new avenue for attempts to develop more specific drugs for the disorder.
© 2007 S. Karger AG, Basel
- Protein kinase C
- Affective disorders
- Animal model
- Growth-associated protein of 43 kDa
- Manji HK, Lenox RH: Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry 2000;48:518–530.
- Bezchlibnyk Y, Young LT: The neurobiology of bipolar disorder: focus on signal transduction pathways and the regulation of gene expression. Can J Psychiatry 2002;47:135–148.
- Coyle JT, Duman RS: Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 2003;38:157–160.
- Payne JL, Quiroz JA, Gould TD, Zarate CA, Manji HK: Neurobiology of bipolar disorder; in Charney DS, Nestler EJ (eds): Neurobiology of Mental Illness. Oxford, Oxford University Press, 2004, pp 397–420.
- Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992;258:607–614.
- Stabel S, Parker PJ: Protein kinase C. Pharmacol Ther 1991;51:71–95.
- Newton AC: Protein kinase C: structure, function, and regulation. J Biol Chem 1995;270:28495–28498.
- Iannazzo L: Involvement of B-50 (GAP-43) phosphorylation in the modulation of transmitter release by protein kinase C. Clin Exp Pharmacol Physiol 2001;28:901–904.
- MacDonald JF, Kotecha SA, Lu WY, Jackson MF: Convergence of PKC-dependent kinase signal cascades on NMDA receptors. Curr Drug Targets 2001;2:299–312.
- Nogues X: Protein kinase C, learning and memory: a circular determinism between physiology and behaviour. Prog Neuropsychopharmacol Biol Psychiatry 1997;21:507–529.
- Ramakers GM, Pasinelli P, Hens JJ, Gispen WH, De Graan PN: Protein kinase C in synaptic plasticity: changes in the in situ phosphorylation state of identified pre- and postsynaptic substrates. Prog Neuropsychopharmacol Biol Psychiatry 1997;21:455–486.
- Huang KP: Role of protein kinase C in cellular regulation. Biofactors 1990;2:171–178.
- Kraft AS, Anderson WB: Phorbol esters increase the amount of Ca2+, phospholipid-dependent protein kinase associated with plasma membrane. Nature 1983;301:621–623.
- Bitran JA, Potter WZ, Manji HK, Gusovsky F: Chronic Li+ attenuates agonist- and phorbol ester-mediated Na+/H+ antiporter activity in HL-60 cells. Eur J Pharmacol 1990;188:193–202.
- Manji HK, Etcheberrigaray R, Chen G, Olds JL: Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme. J Neurochem 1993;61:2303–2310.
- Chen G, Manji HK, Hawver DB, Wright CB, Potter WZ: Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem 1994;63:2361–2364.
- Lenox RH, Watson DG, Patel J, Ellis J: Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 1992;570:333–340.
- Goodwin FK, Jamison KR: Manic Depressive Illness, ed 1. New York, Oxford University Press, 1990.
- Fibiger HC: Neurobiology of depression: focus on dopamine; in Gessa GL, Fratta W, Pani L, Serra G (eds): Depression and Mania: From Neurobiology to Treatment. Adv Biochem Psychopharmacol. New York, Raven Press, 1995, vol 49, pp 1–18.
- Einat H, Kofman O, Belmaker RH: Animal models of bipolar disorder: from a single episode to progressive cycling models; in Myslobodsky M, Weiner I (eds): Contemporary Issues in Modeling Psychopharmacology. Boston, Kluwer Academic Publishers, 2000, pp 165–180.
- Nestler EJ, Gould E, Manji H, Buncan M, Duman RS, Greshenfeld HK, Hen R, Koester S, Lederhendler I, Meaney M, Robbins T, Winsky L, Zalcman S: Preclinical models: status of basic research in depression. Biol Psychiatry 2002;52:503–528.
- Post RM, Contel NR: Cocaine-induced behavioral sensitization: a model for recurrent manic illness; in Perris C, Struwe G, Jansson B (eds): Biological Psychiatry. Amsterdam, Elsevier, 1981, pp 746–749.
- Giambalvo CT: Protein kinase C and dopamine transport. 2. Effects of amphetamine in vitro. Neuropharmacology 1992;31:1211–1222.
- Gnegy ME, Hong P, Ferrell ST: Phosphorylation of neuromodulin in rat striatum after acute and repeated, intermittent amphetamine. Brain Res Mol Brain Res 1993;20:289–298.
- Iwata SI, Hewlett GH, Ferrell ST, Kantor L, Gnegy ME: Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in striatal synaptosomes after repeated amphetamine. J Pharmacol Exp Ther 1997;283:1445–1452.
- Iwata S, Hewlett GH, Gnegy ME: Amphetamine increases the phosphorylation of neuromodulin and synapsin I in rat striatal synaptosomes. Synapse 1997;26:281–291.
- Bebchuk JM, Arfken CL, Dolan-Manji S, Murphy J, Hasanat K, Manji HK: A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch Gen Psychiatry 2000;57:95–97.
- Einat H, Belmaker RH, Manji H: New approaches to modeling bipolar disorder – from face to construct validity. Psychopharmacol Bull 2003;37:47–63.
- Einat H: Modelling facets of mania – new directions related to the notion of endophenotypes. J Psychopharmacol 2006;20:714–722.
- Einat H, Shaldubina A, Bersudsky Y, Belmaker RH: Prospectives for the development of animal models for the study of bipolar disorder; in Soares JC, Young RC (eds): Bipolar Disorders: Basic Mechanisms and Therapeutic Implications, 2nd ed. New York, Informa Healthcare, 2000, pp 23–38.
- O’Brian CA, Ward NE, Anderson BW: Role of specific interactions between protein kinase C and triphenylethylenes in inhibition of the enzyme. J Natl Cancer Inst 1988;80:1628–1633.
- Baltuch GH, Couldwell WT, Villemure JG, Yong VW: Protein kinase C inhibitors suppress cell growth in established and low-passage glioma cell lines: a comparison between staurosporine and tamoxifen. Neurosurgery 1993;33:495–501; discussion 501.
- Oehrlein SA, Parker PJ, Herget T: Phosphorylation of GAP-43 (growth-associated protein of 43 kDa) by conventional, novel and atypical isotypes of the protein kinase C gene family: differences between oligopeptide and polypeptide phosphorylation. Biochem J 1996;317:219–224.
- Dalton JC, Vickers GJ, Roberts DC: Increased self-administration of cocaine following haloperidol: sex-dependent effects of the antiestrogen tamoxifen. Pharmacol Biochem Behav 1986;25:497–501.
- Antoniou K, Kafetzopoulos E, Papadopoulou-Daifoti Z, Hyphantis T, Marselos M: D-Amphetamine, cocaine and caffeine: a comparative study of acute effects on locomotor activity and behavioural patterns in rats. Neurosci Biobehav Rev 1998;23:189–196.
- Golani I, Einat H, Tchernichovski O, Teitelbaum P: Keeping the body straight in the unconstrained locomotion of normal and dopamine-stimulant-treated rats. J Mot Behav 1997;29:99–112.
- Bowling SL, Bardo MT: Locomotor and rewarding effects of amphetamine in enriched, social, and isolate reared rats. Pharmacol Biochem Behav 1994;48:459–464.
- Decker S, Grider G, Cobb M, Li XP, Huff MO, El-Mallakh RS, Levy RS: Open field is more sensitive than automated activity monitor in documenting ouabain-induced hyperlocomotion in the development of an animal model for bipolar illness. Prog Neuropsychopharmacol Biol Psychiatry 2000;24:455–462.
- Chaouloff F, Elghozi JL, Guezennec Y, Laude D: Effects of conditioned running on plasma, liver and brain tryptophan and on brain 5-hydroxytryptamine metabolism of the rat. Br J Pharmacol 1985;86:33–41.
- Aloisi AM, Casamenti F, Scali C, Pepeu G, Carli G: Effects of novelty, pain and stress on hippocampal extracellular acetylcholine levels in male rats. Brain Res 1997;748:219–226.
- Tejero-Diez P, Rodriguez-Sanchez P, Martin-Cofreces NB, Diez-Guerra FJ: bFGF stimulates GAP-43 phosphorylation at ser41 and modifies its intracellular localization in cultured hippocampal neurons. Mol Cell Neurosci 2000;16:766–780.
- Van Hooff CO, Holthuis JC, Oestreicher AB, Boonstra J, De Graan PN, Gispen WH: Nerve growth factor-induced changes in the intracellular localization of the protein kinase C substrate B-50 in pheochromocytoma PC12 cells. J Cell Biol 1989;108:1115–1125.
- Krivanek J: Protein kinase C in the parabrachial nucleus of rats during conditioned taste aversion induced by amphetamine. Neurosci Lett 1997;236:17–20.
- Robinson PJ: The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release. Mol Neurobiol 1991;5:87–130.
- Cowell RM, Kantor L, Hewlett GH, Frey KA, Gnegy ME: Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes. Eur J Pharmacol 2000;389:59–65.
- Kantor L, Gnegy ME: Protein kinase C inhibitors block amphetamine-mediated dopamine release in rat striatal slices. J Pharmacol Exp Ther 1998;284:592–598.
- Zhou J, He R, Johnson KM, Ye Y, Kozikowski AP: Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization. J Med Chem 2004;47:5821–5824.
- Spencer SA, Schuh SM, Liu WS, Willard MB: GAP-43, a protein associated with axon growth, is phosphorylated at three sites in cultured neurons and rat brain. J Biol Chem 1992;267:9059–9064.
- Huang KP, Huang FL, Chen HC: Hypoxia/ischemia induces dephosphorylation of rat brain neuromodulin/GAP-43 in vivo. J Neurochem 1999;72:1294–1306.
- Coggins PJ, Zwiers H: Evidence for a single protein kinase C-mediated phosphorylation site in rat brain protein B-50. J Neurochem 1989;53:1895–1901.
- Park YH, Kantor L, Guptaroy B, Zhang M, Wang KK, Gnegy ME: Repeated amphetamine treatment induces neurite outgrowth and enhanced amphetamine-stimulated dopamine release in rat pheochromocytoma cells (PC12 cells) via a protein kinase C- and mitogen activated protein kinase-dependent mechanism. J Neurochem 2003;87:1546–1557.
- Young E, Cesena T, Meiri KF, Perrone-Bizzozero NI: Changes in protein kinase C (PKC) activity, isozyme translocation, and GAP-43 phosphorylation in the rat hippocampal formation after a single-trial contextual fear conditioning paradigm. Hippocampus 2002;12:457–464.
- Willner P: Animal models of depression: validity and applications; in Gessa GL, Fratta W, Pani L, Serra G (eds): Depression and Mania: From Neurobiology to Treatment. Adv Biochem Psychopharmacol. New York, Raven Press, 1995, vol 49, pp 19–42.
- Mandlekar S, Kong AN: Mechanisms of tamoxifen-induced apoptosis. Apoptosis 2001;6:469–477.
- Jordan VC: Overview from the International Conference on Long-Term Tamoxifen Therapy for Breast Cancer. J Natl Cancer Inst 1992;84:231–234.
- Jordan VC: Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2003;2:205–213.
- Goekjian PG, Jirousek MR: Protein kinase C inhibitors as novel anticancer drugs. Expert Opin Investig Drugs 2001;10:2117–2140.
- Wheeler GD: Ruboxistaurin (Eli Lilly). IDrugs 2003;6:159–163.
- Pollack IF, DaRosso RC, Robertson PL, Jakacki RL, Mirro JR Jr, Blatt J, Nicholson S, Packer RJ, Allen JC, Cisneros A, Jordan VC: A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood. Clin Cancer Res 1997;3:1109–1115.
- Mastronardi L, Puzzilli F, Ruggeri A: Tamoxifen as a potential treatment of glioma. Anticancer Drugs 1998;9:581–586.
- Couldwell WT, Hinton DR, Surnock AA, DeGiorgio CM, Weiner LP, Apuzzo ML, Masri L, Law RE, Weiss MH: Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 1996;2:619–622.
- Browman KE, Kantor L, Richardson S, Badiani A, Robinson TE, Gnegy ME: 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 1998;814:112–119.
- Steketee JD: Intra-ventral tegmental area administration of H7 delays, but does not prevent the development of cocaine-induced sensitization. Brain Res Bull 1997;43:565–571.
- Steketee JD: Intra-A10 injection of H7 blocks the development of sensitization to cocaine. Neuroreport 1994;6:69–72.
- Steketee JD: 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 1993;32:1289–1297.
- Kamei J, Mizoguchi H, Narita M, Tseng LF: Therapeutic potential of PKC inhibitors in painful diabetic neuropathy. Expert Opin Investig Drugs 2001;10:1653–1664.
- Cervo L, Mukherjee S, Bertaglia A, Samanin R: Protein kinases A and C are involved in the mechanisms underlying consolidation of cocaine place conditioning. Brain Res 1997;775:30–36.
- Einat H, Chen G, Manji H: Possible involvement of protein kinase C (PKC) in bipolar disorder and its treatment. Harefuah 2004;143:420–425.
- Einat H, Manji HK: Cellular plasticity cascades: gene to behavior pathways in animal models of bipolar disorder. Biol Psychiatry 2006;59:1960–1971.
- Birnbaum SG, Yuan PX, Wang M, Vijayraghavan S, Bloom AK, Davis DJ, Gobeske KT, Sweatt JD, Manji HK, Arnsten AF: Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 2004;306:882–884.
- Menniti FS, Baum MJ: Differential effects of estrogen and androgen on locomotor activity induced in castrated male rats by amphetamine, a novel environment, or apomorphine. Brain Res 1981;216:89–107.
- West CH, Michael RP: Time-dependent modulation by estrogen of amphetamine-induced hyperactivity in male rats. Pharmacol Biochem Behav 1986;25:919–923.
- Castner SA, Xiao L, Becker JB: Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies. Brain Res 1993;610:127–134.
- Earley CJ, Leonard BE: Behavioural studies on the effects of d-amphetamine and estradiol benzoate alone and in combination. Psychopharmacology (Berl) 1978;56:179–183.
- Friedman E, Hoau Yan W, Levinson D, Connell TA, Singh H: Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 1993;33:520–525.
- Hahn CG, Umapathy, Wang HY, Koneru R, Levinson DF, Friedman E: Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. J Psychiatr Res 2005;39:355–363.
- Wang HY, Friedman E: Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry 1996;40:568–575.
- Giambalvo CT: Protein kinase C and dopamine transport-1. Effects of amphetamine in vivo. Neuropharmacology 1992;31:1201–1210.
- Lenox RH, Wang L: Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Mol Psychiatry 2003;8:135–144.
- Manji HK, Lenox RH: 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 1999;46:1328–1351.
Haim Einat, PhD
University of Minnesota, College of Pharmacy, Duluth
376 Kirby Plaza, 1208 Kirby Dr.
Duluth, MN 55812 (USA)
Tel. +1 218 726 6029, Fax +1 218 726 6500, E-Mail firstname.lastname@example.org
Received: November 10, 2006
Accepted after revision: March 24, 2007
Published online: July 18, 2007
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 2, Number of References : 80
Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)
Vol. 55, No. 3-4, Year 2007 (Cover Date: October 2007)
Journal Editor: Strik, W. (Bern)
ISSN: 0302–282X (print), 1423–0224 (Online)
For additional information: http://www.karger.com/NPS
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.