Skip to main content
SpringerLink
Log in

Proteome analysis after co-administration of clozapine or haloperidol to MK-801-treated rats

  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary

MK-801, a glutamergic, N-methyl-D-aspartate (NMDA)-receptor antagonist that mediates neurotransmission and has psychotomimetic properties, giving schizophrenia-like symptom. The objective of this study was to investigate the effects on the thalamic and cortical proteome of one typical (haloperidol) and one atypical (clozapine) antipsychotic drug in interaction with MK-801 in rats. Rats received subcutaneous injections of MK-801 or vehicle (controls) or MK-801 together with concurrent administration of haloperdol or clozapine for eight days. Protein samples from thalamus and cortex were analyzed with two-dimensional gel electrophoresis in combination with mass spectrometry. MK-801 induced alterations in the levels of three proteins in both cortex and thalamus. Clozapine reversed all the protein changes. Haloperidol reversed two. Both antipsychotics induced new protein changes in both cortex and thalamus not seen after MK-801-treatment by alone. In conclusion, the MK-801 animal model shows potential for investigation of different antipsychotic drugs and biochemical treatment effects in schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • M Amargos-Bosch X Lopez-Gil F Artigas A Adell (2006) ArticleTitleClozapine and olanzapine, but not haloperidol, suppress serotonine efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine Int J Neuropsychopharmacol 9 565–573 Occurrence Handle16316487 Occurrence Handle10.1017/S1461145705005900 Occurrence Handle1:CAS:528:DC%2BD28XhtFKku73K

    Article  PubMed  CAS  Google Scholar 

  • A Andres J Satrustegui A Machado (1983) ArticleTitleDevelopment of NADPH-consuming pathways in heart, brain and liver of the rat Biol Neonate 43 198–204 Occurrence Handle6407538 Occurrence Handle1:CAS:528:DyaL3sXhvFGmu7k%3D Occurrence Handle10.1159/000241629

    Article  PubMed  CAS  Google Scholar 

  • S Behrens WF Gattaz (1992) ArticleTitleMK-801 induced stereotypes in rats are decreased by haloperidol and increased by diazepam J Neural Transm Gen Sect 90 219–224 Occurrence Handle1285950 Occurrence Handle10.1007/BF01250962 Occurrence Handle1:CAS:528:DyaK3sXisVOns7s%3D

    Article  PubMed  CAS  Google Scholar 

  • D Ben-Shachar (2002) ArticleTitleMitochondrial dysfunction in schizophrenia: a possible linkage to dopamine J Neurochem 83 1241–1251 Occurrence Handle12472879 Occurrence Handle10.1046/j.1471-4159.2002.01263.x Occurrence Handle1:CAS:528:DC%2BD3sXjsFGr

    Article  PubMed  CAS  Google Scholar 

  • P Bubber J Tang V Haroutunian H Xu KL Davis JP Blass GE Gibson (2004) ArticleTitleMitochondrial enzymes in schizophrenia J Mol Neurosci 24 315–321 Occurrence Handle15456945 Occurrence Handle10.1385/JMN:24:2:315 Occurrence Handle1:CAS:528:DC%2BD2cXptVyjsLY%3D

    Article  PubMed  CAS  Google Scholar 

  • B Capuano IT Crosby EJ Lloyd (2002) ArticleTitleSchizophrenia: genesis, receptorology and current therapeutics Curr Med Chem 9 521–548 Occurrence Handle11945123 Occurrence Handle10.2174/0929867024606939 Occurrence Handle1:CAS:528:DC%2BD38XislGmt70%3D

    Article  PubMed  CAS  Google Scholar 

  • A Carlsson (1988) ArticleTitleThe current status of the dopamine hypothesis of schizophrenia Neuropsychopharmacology 1 179–186 Occurrence Handle3075131 Occurrence Handle10.1016/0893-133X(88)90012-7 Occurrence Handle1:STN:280:DyaL1M3os1ymtQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • A Carlsson M Lindqvist (1973) ArticleTitleEffect of ethanol on the hydroxylation of tyrosine and tryptophan in rat brain in vivo J Pharm Pharmacol 25 437–440 Occurrence Handle4146580 Occurrence Handle1:CAS:528:DyaE3sXltVWjtbo%3D

    PubMed  CAS  Google Scholar 

  • M Carlsson A Carlsson (1990) ArticleTitleInteractions between glutamatergic and monoaminergic systems within the basal ganglia – implications for schizophrenia and Parkinson’s disease Trends Neurosci 13 272–276 Occurrence Handle1695402 Occurrence Handle10.1016/0166-2236(90)90108-M Occurrence Handle1:CAS:528:DyaK3MXjs1Smsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • ML Carlsson A Carlsson M Nilsson (2004) ArticleTitleSchizophrenia: from dopamine to glutamate and back Curr Med Chem 11 267–277 Occurrence Handle14965231 Occurrence Handle10.2174/0929867043456034 Occurrence Handle1:CAS:528:DC%2BD2cXhs1Sqsrw%3D

    Article  PubMed  CAS  Google Scholar 

  • P Carninci Y Hayashizaki (1999) ArticleTitleHigh-efficiency full-length cDNA cloning Method Enzymol 303 19–44 Occurrence Handle1:CAS:528:DyaK1MXltFOnsro%3D Occurrence Handle10.1016/S0076-6879(99)03004-9

    Article  CAS  Google Scholar 

  • DF Condorelli VG Nicoletti V Barresi SG Conticello A Caruso EA Tendi AM Giuffrida Stella (1999) ArticleTitleStructural features of the rat GFAP gene and identification of a novel alternative transcript J Neurosci Res 56 219–228 Occurrence Handle10336251 Occurrence Handle10.1002/(SICI)1097-4547(19990501)56:3<219::AID-JNR1>3.0.CO;2-2 Occurrence Handle1:CAS:528:DyaK1MXivVOhtLg%3D

    Article  PubMed  CAS  Google Scholar 

  • R Corbett (1995) ArticleTitleClozapine but not haloperidol antagonizes an MK-801 discriminative stimulus cue Pharmacol Biochem Behav 51 561–564 Occurrence Handle7667388 Occurrence Handle10.1016/0091-3057(95)00072-5 Occurrence Handle1:CAS:528:DyaK2MXlvFyltL8%3D

    Article  PubMed  CAS  Google Scholar 

  • JT Coyle G Tsai (2004) ArticleTitleNMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia Int Rev Neurobiol 59 491–515 Occurrence Handle15006500 Occurrence Handle1:CAS:528:DC%2BD2cXktVertbc%3D Occurrence Handle10.1016/S0074-7742(04)59019-0

    Article  PubMed  CAS  Google Scholar 

  • MJ Dunn S Killcross (2006a) ArticleTitleDifferential attenuation of d-amphetamine-induced disruption of conditional discrimination performance by dopamine and serotonine antagonists Psychopharmacology (Berl) 188 183–192 Occurrence Handle10.1007/s00213-006-0488-y Occurrence Handle1:CAS:528:DC%2BD28Xpt1Ontbg%3D

    Article  CAS  Google Scholar 

  • MJ Dunn S Killcross (2006b) ArticleTitleClozapine but not haloperidol treatment reverses sub-chronic phencycledine-induced disruption of conditional discrimination performance Behav Brain Res 175 271–277 Occurrence Handle10.1016/j.bbr.2006.08.028 Occurrence Handle1:CAS:528:DC%2BD28Xht1ersr7F

    Article  CAS  Google Scholar 

  • G Ellison (1995) ArticleTitleThe N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias Brain Res Rev 20 250–267 Occurrence Handle7795658 Occurrence Handle10.1016/0165-0173(94)00014-G Occurrence Handle1:CAS:528:DyaK2MXlsVCnur4%3D

    Article  PubMed  CAS  Google Scholar 

  • NB Farber J Foster NL Duhan JW Olney (1996) ArticleTitleOlanzapine and fluperlapine mimic clozapine in preventing MK-801 neurotoxicity Schizophr Res 21 33–37 Occurrence Handle8998274 Occurrence Handle10.1016/0920-9964(96)00024-2 Occurrence Handle1:STN:280:DyaK2s7kvVGjuw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • KH Fliegner GY Ching RK Liem (1990) ArticleTitleThe predicted amino acid sequence of alpha-internexin is that of a novel neuronal intermediate filament protein Embo J 9 749–755 Occurrence Handle2311576 Occurrence Handle1:CAS:528:DyaK3cXlt1yhsL0%3D

    PubMed  CAS  Google Scholar 

  • AA Grace (1991) ArticleTitlePhasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia Neuroscience 41 1–24 Occurrence Handle1676137 Occurrence Handle10.1016/0306-4522(91)90196-U Occurrence Handle1:CAS:528:DyaK3MXisVGiur8%3D

    Article  PubMed  CAS  Google Scholar 

  • DC Hoffman (1992) ArticleTitleTypical and atypical neuroleptics antagonize MK-801-induced locomotion and stereotypy in rats J Neural Transm Gen Sect 89 1–10 Occurrence Handle1358122 Occurrence Handle10.1007/BF01245347 Occurrence Handle1:CAS:528:DyaK3sXhtlw%3D

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC, Zukin SR (1991a) Mechanisms of phencyclidine (PCP)-N-aspartate receptor interaction: implications for schizophrenia. Schizophrenia research progress: 12–19

  • DC Javitt SR Zukin (1991b) ArticleTitleRecent advances in the phencyclidine model of schizophrenia [see comments] Am J Psychiatry 148 1301–1308 Occurrence Handle1:STN:280:DyaK3MznslymsA%3D%3D

    CAS  Google Scholar 

  • NL Johnston-Wilson CD Sims JP Hofmann L Anderson AD Shore EF Torrey RH Yolken (2000) ArticleTitleDisease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium Mol Psychiatry 5 142–149 Occurrence Handle10822341 Occurrence Handle10.1038/sj.mp.4000696 Occurrence Handle1:CAS:528:DC%2BD3cXlslartrg%3D

    Article  PubMed  CAS  Google Scholar 

  • JS Kim HH Kornhuber W Schmid-Burgk B Holzmuller (1980) ArticleTitleLow cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia Neurosci Lett 20 379–382 Occurrence Handle6108541 Occurrence Handle10.1016/0304-3940(80)90178-0 Occurrence Handle1:CAS:528:DyaL3MXhtlOksA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • O Koul JE March R Sarma C Griffiths DG Deutsch (1986) ArticleTitleEffect of phencyclidine on the metabolism of individual brain proteins J Neurochem 46 470–474 Occurrence Handle3941317 Occurrence Handle10.1111/j.1471-4159.1986.tb12991.x Occurrence Handle1:CAS:528:DyaL28XotF2rsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • S Lin AG McLennan K Ying Z Wang S Gu H Jin C Wu W Liu Y Yuan R Tang Y Xie Y Mao (2001) ArticleTitleCloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the itpa gene J Biol Chem 276 18695–18701 Occurrence Handle11278832 Occurrence Handle10.1074/jbc.M011084200 Occurrence Handle1:CAS:528:DC%2BD3MXkt12kt74%3D

    Article  PubMed  CAS  Google Scholar 

  • Y Makino S Yogosawa M Kanemaki T Yoshida K Yamano T Kishimoto V Moncollin JM Egly M Muramatsu T Tamura (1996) ArticleTitleStructures of the rat proteasomal ATPases: determination of highly conserved structural motifs and rules for their spacing Biochem Biophys Res Commun 220 1049–1054 Occurrence Handle8607789 Occurrence Handle10.1006/bbrc.1996.0530 Occurrence Handle1:CAS:528:DyaK28Xit1Kmur8%3D

    Article  PubMed  CAS  Google Scholar 

  • RM Marchbanks J Mulcrone SA Whatley (1995) ArticleTitleAspects of oxidative metabolism in schizophrenia Br J Psychiatry 167 293–298 Occurrence Handle7496636 Occurrence Handle1:STN:280:DyaK28%2Fpt1ynsQ%3D%3D

    PubMed  CAS  Google Scholar 

  • I Maurer S Zierz H Moller (2001) ArticleTitleEvidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia Schizophr Res 48 125–136 Occurrence Handle11278159 Occurrence Handle10.1016/S0920-9964(00)00075-X Occurrence Handle1:STN:280:DC%2BD3M7ovF2mtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • RE McCullumsmith SM Clinton JH Meador-Woodruff (2004) ArticleTitleSchizophrenia as a disorder of neuroplasticity Int Rev Neurobiol 59 19–45 Occurrence Handle15006483 Occurrence Handle1:CAS:528:DC%2BD2cXktVert70%3D

    PubMed  CAS  Google Scholar 

  • M Nilsson S Waters N Waters A Carlsson ML Carlsson (2001) ArticleTitleA behavioural pattern analysis of hypoglutamatergic mice – effects of four different antipsychotic agents J Neural Transm 108 1181–1196 Occurrence Handle11725821 Occurrence Handle10.1007/s007020170008 Occurrence Handle1:CAS:528:DC%2BD38XjvVSjuw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • JW Olney NB Farber (1995) ArticleTitleGlutamate receptor dysfunction and schizophrenia Arch Gen Psychiatry 52 998–1007 Occurrence Handle7492260 Occurrence Handle1:CAS:528:DyaK28XotF2rtA%3D%3D

    PubMed  CAS  Google Scholar 

  • L Paulson P Martin A Persson CL Nilsson E Ljung A Brinkmalm-Westman P Eriksson K Blennow P Davidsson (2003) ArticleTitleComparative genome- and proteome analysis of cerebral cortex from MK-801 treated rats J Neurosci Res 71 526–533 Occurrence Handle12548708 Occurrence Handle10.1002/jnr.10509 Occurrence Handle1:CAS:528:DC%2BD3sXptVKgtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • L Paulson P Martin E Ljung K Blennow P Davidsson (2004a) ArticleTitleEffects on rat thalamic proteome by acute and subchronic MK-801-treatment Eur J Pharmacol 505 103–109 Occurrence Handle10.1016/j.ejphar.2004.10.036 Occurrence Handle1:CAS:528:DC%2BD2cXhtVWjsLbE

    Article  CAS  Google Scholar 

  • L Paulson P Martin CL Nilsson E Ljung A Westman-Brinkmalm K Blennow P Davidsson (2004b) ArticleTitleComparative proteome analysis of thalamus in MK-801-treated rats Proteomics 4 819–825 Occurrence Handle10.1002/pmic.200300622 Occurrence Handle1:CAS:528:DC%2BD2cXitlCisrw%3D

    Article  CAS  Google Scholar 

  • JA Prince K Blennow CG Gottfries I Karlsson L Oreland (1999) ArticleTitleMitochondrial function is differentially altered in the basal ganglia of chronic schizophrenics Neuropsychopharmacology 21 372–379 Occurrence Handle10457534 Occurrence Handle10.1016/S0893-133X(99)00016-0 Occurrence Handle1:STN:280:DyaK1MzosF2rtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • M Schuerenberg C Luebbert H Eickhoff M Kalkum H Lehrach E Nordhoff (2000) ArticleTitlePrestructured MALDI-MS sample supports Anal Chem 72 3436–3442 Occurrence Handle10952524 Occurrence Handle10.1021/ac000092a Occurrence Handle1:CAS:528:DC%2BD3cXksVagtL4%3D

    Article  PubMed  CAS  Google Scholar 

  • C Sur PJ Mallorga M Wittman MA Jacobson D Pascarella JB Williams PE Brandish DJ Pettibone EM Scolnick PJ Conn (2003) ArticleTitleN-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentates N-methyl-D-aspartate receptor activity PNAS 100 IssueID23 13674–13679 Occurrence Handle14595031 Occurrence Handle10.1073/pnas.1835612100 Occurrence Handle1:CAS:528:DC%2BD3sXptFOitbY%3D

    Article  PubMed  CAS  Google Scholar 

  • CA Tamminga HH Holcomb XM Gao AC Lahti (1995) ArticleTitleGlutamate pharmacology and the treatment of schizophrenia: current status and future directions Int Clin Psychopharmacol 10 IssueIDSuppl 3 29–37 Occurrence Handle8866763 Occurrence Handle10.1097/00004850-199509000-00005

    Article  PubMed  Google Scholar 

  • PI Tiedtke C Bischoff WJ Schmidt (1990) ArticleTitleMK-801-induced stereotypy and its antagonism by neuroleptic drugs J Neural Trans Gen Sect 81 173–182 Occurrence Handle10.1007/BF01245040 Occurrence Handle1:CAS:528:DyaK3MXmt1ehtb0%3D

    Article  CAS  Google Scholar 

  • E Umlauf E Csaszar M Moertelmaier GJ Schuetz RG Parton R Prohaska (2004) ArticleTitleAssociation of stomatin with lipid bodies J Biol Chem 279 23699–23709 Occurrence Handle15024010 Occurrence Handle10.1074/jbc.M310546200 Occurrence Handle1:CAS:528:DC%2BD2cXkt1Giu74%3D

    Article  PubMed  CAS  Google Scholar 

  • MJ Webster J O’Grady JE Kleinman CS Weickert (2005) ArticleTitleGlial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia Neuroscience 133 453–461 Occurrence Handle15885920 Occurrence Handle10.1016/j.neuroscience.2005.02.037 Occurrence Handle1:CAS:528:DC%2BD2MXks1GnsLw%3D

    Article  PubMed  CAS  Google Scholar 

  • SA Whatley D Curti RM Marchbanks (1996) ArticleTitleMitochondrial involvement in schizophrenia and other functional psychoses Neurochem Res 21 995–1004 Occurrence Handle8897462 Occurrence Handle10.1007/BF02532409 Occurrence Handle1:CAS:528:DyaK28Xmt12hu7g%3D

    Article  PubMed  CAS  Google Scholar 

  • ZA Wood E Schroder J Robin Harris LB Poole (2003) ArticleTitleStructure, mechanism and regulation of peroxiredoxins Trends Biochem Sci 28 32–40 Occurrence Handle12517450 Occurrence Handle10.1016/S0968-0004(02)00003-8 Occurrence Handle1:CAS:528:DC%2BD3sXnvFGh

    Article  PubMed  CAS  Google Scholar 

  • SJ Yeaman (1989) ArticleTitleThe 2-oxo acid dehydrogenase complexes: recent advances Biochem J 257 625–632 Occurrence Handle2649080 Occurrence Handle1:CAS:528:DyaL1MXhsFSitLg%3D

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Neuroscience and Physiology, Göteborg University, Mölndal, Sweden

    L. Paulson, K. Blennow & P. Davidsson

  2. Carlsson Research AB, Göteborg, Sweden

    P. Martin & E. Ljung

  3. Department of Experimental Medicine/Molecular Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden

    P. Davidsson

Authors
  1. L. Paulson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Ljung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Blennow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Davidsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paulson, L., Martin, P., Ljung, E. et al. Proteome analysis after co-administration of clozapine or haloperidol to MK-801-treated rats. J Neural Transm 114, 885–891 (2007). https://doi.org/10.1007/s00702-007-0626-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-007-0626-7

Search

Navigation