Skip to main content
SpringerLink
Log in

Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rational

Negative symptoms of schizophrenia are insufficiently treated by current antipsychotics. However, research is limited by the lack of validated models. Clinical data indicate that phencyclidine (PCP) abuse may induce symptoms resembling negative symptoms in humans. Based on that, Noda et al. proposed a model of PCP-induced increase of immobility in the forced swim test in mice as a model of depression-like negative symptoms of schizophrenia.

Objectives

The aim of the study was to evaluate the effect of phosphodiesterase 10A (PDE10A) inhibition in this model which was modified by using MK-801 instead of PCP.

Methods

Increase of immobility in the forced swim test was induced by repeated MK-801 treatment followed by a 2-day washout in mice. The effect of haloperidol, clozapine, risperidone and PDE10A inhibitors was evaluated in this model, on open-field activity and acute MK-801-induced hyperactivity.

Results

Repeated MK-801 treatment significantly increased immobility in the forced swim test without affecting open-field activity. It induced hypersensitivity to the dopamine D1 agonist A-68930, suggesting a hypofunction of the D1 pathway. The increase of immobility is reversed by clozapine and PDE10A inhibitors, but not by haloperidol. Clozapine and the PDE10A inhibitors did not enhance activity at effective doses.

Conclusion

The possibility to substitute PCP by MK-801 in this model indicates that the effect is mediated by their common mechanism of NMDA antagonism. PDE10A inhibitors similar to clozapine significantly antagonize the increase of immobility, suggesting a therapeutic potential for the treatment of negative symptoms. However, further validation of the model is necessary.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Abi-Saab WM, D’Souza DC, Moghaddam B, Krystal JH (1998) The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 31(Suppl 2):104–109. doi:10.1055/s-2007-979354-x

    Article  PubMed  CAS  Google Scholar 

  • Allen RM, Young SJ (1978) Phencyclidine-induced psychosis. Am J Psychiatry 135:1081–1084

    PubMed  CAS  Google Scholar 

  • Anastasio NC, Johnson KM (2008) Differential regulation of the NMDA receptor by acute and sub-chronic phencyclidine administration in the developing rat. J Neurochem 104:1210–1218. doi:10.1111/j.1471-4159.2007.05047

    Article  PubMed  CAS  Google Scholar 

  • Andiné P, Widermark N, Axelsson R, Nyberg G, Olofsson U, Martensson E, Sandberg M (1999) Characterization of MK-801-induced behavior as a putative rat model of psychosis. J Pharmacol Exp Ther 290:1393–1408

    PubMed  Google Scholar 

  • Arvanov VL, Wang RY (1999) Clozapine, but not haloperidol, prevents the functional hyperactivity of N-methyl-D-aspartate receptors in rat cortical neurons induced by subchronic administration of phencyclidine. J Pharmacol Exp Ther 289:1000–1006

    PubMed  CAS  Google Scholar 

  • Audet MC, Goulet S, Doré FY (2009) Impaired social motivation and increased aggression in rats subchronically exposed to phencyclidine. Physiol Behav 96:394–398. doi:10.1016/j.physbeh.2008.11.002

    Article  PubMed  CAS  Google Scholar 

  • Barnett JH, Robbins TW, Leeson VC, Sahakian BJ, Joyce EM, Blackwell AD (2010) Assessing cognitive function in clinical trials of schizophrenia. Neurosci Biobehav Rev 34:1161–1177. doi:10.1016/j.neubiorev.2010.01.012

    Article  PubMed  Google Scholar 

  • Benes FM (1993) The relationship between structural brain imaging and histopathologic findings in schizophrenia research. Harv Rev Psychiatry 1:100–109

    Article  PubMed  CAS  Google Scholar 

  • bi-Dargham A (2003) Probing cortical dopamine function in schizophrenia: what can D1 receptors tell us? World Psychiatry 2:166–171

    Google Scholar 

  • Brar JS, Chengappa KN, Parepally H, Sandman AR, Kreinbrook SB, Sheth SA, Ganguli R (1997) The effect of clozapine on negative symptoms in patients with schizophrenia with minimla positive symptoms. Ann Clin Psychiatry 9:227–234

    PubMed  CAS  Google Scholar 

  • Capuano B, Crosby IT, Lloyd EJ (2002) Schizophrenia: genesis, receptorology and current therapeutics. Curr Med Chem 9:521–548

    Article  PubMed  CAS  Google Scholar 

  • Cardno AG, Jones LA, Murphy KC, Asherson P, Scott LC, Williams J, Owen MJ, McGuffin P (1996) Factor analysis of schizophrenic symptoms using the OPCRIT checklist. Schizophr Res 22:233–239

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee M, Ganguly S, Srivastava M, Palit G (2011) Effect of “chronic” versus “acute” ketamine administration and its withdrawal effect on behavioural alterations in mice: implications for experimental psychosis. Behav Brain Res 216:247–254. doi:10.1016/j.bbr.2010.08.001

    Article  PubMed  CAS  Google Scholar 

  • Corbett R, Zhou L, Sorensen SM, Mondadori C (1999) Animal models of negative symptoms: M100907 antagonizes PCP-induced immobility in a forced swim test in mice. Neuropsychopharm 21:S211–S218

    Article  CAS  Google Scholar 

  • Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245. doi:10.1016/SO165-6147(02)02017-5

    Article  PubMed  CAS  Google Scholar 

  • De Angelis GG, Goldstein E (1978) Treatment of adolescent phencyclidine (PCP) abusers. Am J Drug Alcohol Abuse 5:399–414

    Article  PubMed  Google Scholar 

  • Ereshefsky L, Watanabe MD, Tran-Johnson TK (1989) Clozapine: an atypical antipsychotic agent. Clin Pharm 8:691–709

    PubMed  CAS  Google Scholar 

  • Garey RE (1979) PCP (phencyclidine): an update. J Psychedelic Drugs 11:265–275

    Article  PubMed  CAS  Google Scholar 

  • Gilmour G, Pioli EY, Dix SL, Smith JW, Conway MW, Jones WT, Loomis S, Mason R, Shahabi S, Tricklebank MD (2009) Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for "NMDA antagonist modelling" of schizophrenia. Psychopharmacology 205:203–216. doi:10.1007/s00213-009-1530-7

    Article  PubMed  CAS  Google Scholar 

  • Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, Langen B, Logue S, Brennan J, Jiang L, Charych E, Egerland U, Liu F, Marquis KL, Malamas M, Hage T, Comery TA, Brandon NJ (2009) Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther 331:574–590. doi:10.1124/jpet.109.155994

    Article  PubMed  CAS  Google Scholar 

  • Hoefgen N, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, Egerland U, Tremmel P, Pangalos MN, Marquis KL, Hage T, Harrison BL, Malamas MS, Brandon NJ, Kronbach T (2010) Discovery of imidazo[1,5a]pyrido[3,2e]pyrazines as a new class of phosphodiesterase 10A inhibitors. J Med Chem 53:4399–4411. doi:10.1021/jm1002793

    Article  CAS  Google Scholar 

  • Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225

    Article  PubMed  CAS  Google Scholar 

  • Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Article  PubMed  CAS  Google Scholar 

  • Langen B, Egerland U, Bernoester K, Dost R, Unverferth K, Rundfeldt C (2005) Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor. J Pharmacol Exp Ther 314:717–724. doi:10.1124/jpet.105.084681

    Article  PubMed  CAS  Google Scholar 

  • Liu F, Zou X, Sadovova N, Zhang X, Shi L, Guo L, Qian F, Wen Z, Patterson TA, Hanig JP, Paule MG, Wjr S, Wang C (2011) Changes in gene expression after phencyclidine administration in developing rats: a potential animal model for schizophrenia. Int Dev Neurosci 29:351–358. doi:10.1016/j.ijdevneu.2010.07.234

    Article  CAS  Google Scholar 

  • Miller DD, Perry PJ, Cadoret RJ, Andreasen NC (1994) Clozapine’s effect on negative symptoms in treatment-refractory schizophrenics. Compr Psychiatry 35:8–15

    Article  PubMed  CAS  Google Scholar 

  • Mouri A, Noda Y, Enomoto T, Nabeshima T (2007) Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment. Neurochem Int 51:173–184. doi:10.1016/j.neuint.2007.06.019

    Article  PubMed  CAS  Google Scholar 

  • Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106–118

    Article  PubMed  CAS  Google Scholar 

  • Noda Y, Yamada K, Furukawa H, Nabeshima T (1995) Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. Brit J Pharmacol 116:2531–2537

    CAS  Google Scholar 

  • Noda Y, Mamiya T, Furukawa H, Nabeshima T (1997) Effects of antidepressants on phencyclidine-induced enhancement of immobility in a forced swimming test in mice. Eur J Pharmacol 324:135–140

    Article  PubMed  CAS  Google Scholar 

  • Noda Y, Kamei H, Mamiya T, Furukawa H, Nabeshima T (2000) Repeated phencyclidine treatment induces negative symptom-like behaviour in forced swimming test in mice: imbalance of prefrontal serotonergic and dopaminergic functions. Neuropsychopharmacology 23:375–387. doi:10.1038/sj.npp.1395546

    Article  PubMed  CAS  Google Scholar 

  • Pickar D, Owen RR, Litman RE, Konicki E, Gutierrez R, Rapaport MH (1992) Clinical and biological response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry 49:345–353

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    PubMed  CAS  Google Scholar 

  • Qiao H, Noda Y, Kamei H, Nagai T, Furukawa H, Miura H, Kayukawa Y, Ohta T, Nabeshima T (2001) Clozapine, but not haloperidol, reverses social behavior deficit in mice during withdrawal from chronic phencyclidine treatment. Neuroreport 12:11–15

    Article  PubMed  CAS  Google Scholar 

  • Rey ER, Bailer J, Bräuer W, Händel M, Laubenstein D, Stein A (1994) Stability trends and longitudinal correlations of negative and positive syndromes within a three-year follow-up of initially hospitalized schizophrenics. Acta Psychitr Scand 90:405–412

    Article  CAS  Google Scholar 

  • Sams-Dodd F (1996) Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia. Behav Pharmacol 7:3–23

    PubMed  CAS  Google Scholar 

  • Sams-Dodd F (1998) Effects of continuous D-amphetamine and phencyclidine administration on social behaviour, stereotyped behaviour, and locomotor activity in rats. Neuropsychopharmacology 19:18–25

    Article  PubMed  CAS  Google Scholar 

  • Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, Hoffman WE, Lebel LA, McCarthy SA, Nelson FR, Proulx-LaFrance C, Majchrzak MJ, Ramirez AD, Schmidt K, Seymour PA, Siuciak JA, Tingley FD, Williams RD, Verhoest PR, Menniti FS (2008) Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 325:681–690. doi:10.1124/jpet.107.132910

    Article  PubMed  CAS  Google Scholar 

  • Seillier A, Giuffrida A (2009) Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. Behav Brain Res 204:410–415. doi:10.1016/j.bbr.2009.02.007

    Article  PubMed  CAS  Google Scholar 

  • Siuciak JA, McCarthy SA, Chapin DS, Fujiwara RA, James LC, Williams RD, Stock JL, McNeish JD, Strick CA, Menniti FS, Schmidt CJ (2006) Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. Neuropharmacology 51:374–385. doi:10.1016/j.neuropharm.2006.01.012

    Article  PubMed  CAS  Google Scholar 

  • Smith HP, Nichols DE, Mailman RB, Lawler CP (1997) Locomotor inhibition, yawning and vacuous chewing induced by a novel dopamine D2 post-synaptic receptor agonist. Eur J Pharmacol 323:27–36

    Article  PubMed  CAS  Google Scholar 

  • Sotty F, Montezinho LP, Steiniger-Brach B, Nielsen J (2009) Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons. J Neurochem 109:766–775. doi:10.1111/j.1471-1459.2009.06004.x

    Article  PubMed  CAS  Google Scholar 

  • Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino EF (2005) Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropsychopharmacology 30:1861–1869. doi:10.1038/sj.npp.1300732

    Article  PubMed  CAS  Google Scholar 

  • Young JW, Powell S, Risbrough V, Marston HM, Geyer MA (2009) Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 122:150–202. doi:10.1016/j.pharmthera.2009.02.004

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The study was supported by European Fund for Regional Development (EFRE) and by the Free State of Saxony (grant no. SAB12525). The excellent technical assistance of Doris Zschaber is highly appreciated. Sincere thanks also to Karen Marquis who supported the work with a lot of critical comments. The experiments comply with the current laws of the country in which they were performed.

Author information

Authors and Affiliations

  1. biocrea GmbH, Radebeul, Germany

    Barbara Langen, Rita Dost, Ute Egerland, Hans Stange & Norbert Hoefgen

Authors
  1. Barbara Langen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rita Dost
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ute Egerland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hans Stange
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norbert Hoefgen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Barbara Langen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Langen, B., Dost, R., Egerland, U. et al. Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test. Psychopharmacology 221, 249–259 (2012). https://doi.org/10.1007/s00213-011-2567-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2567-y

Keywords

Search

Navigation