Skip to main content
SpringerLink
Log in

Developing translational animal models for symptoms of schizophrenia or bipolar mania

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Animal models have long been used to explore hypotheses regarding the neurobiological substrates of and treatments for psychiatric disorders. Early attempts to develop models that mimic the entirety of the diagnostic syndromes in psychiatry have evolved into more appropriate efforts to model specific symptoms. Such an approach reflects the facts that even in patients, clinical symptoms transcend diagnostic categories, and the specific etiologies of psychiatric disorders are unknown. An animal model can only be identified adequately by specifying both the manipulation (drug, lesion, strain) used to induce abnormalities and the measure(s) used to characterize them. A wide range of pharmacological, lesion, and developmental manipulations have been combined with various measures of information processing to develop useful animal models that parallel human tests. Prepulse inhibition of startle, event-related potential (ERP) measures of auditory gating, and Cambridge neuropsychological test automated battery (CANTAB) measures of cognition are examples of measures that can be used in both rodents and humans and that are robustly altered in both psychiatric disorders and animals manipulated with appropriate drugs or lesions.

The further development of cross-species models is critically important, given the new opportunities for the development and registration of specific treatments for the cognitive disorders of schizophrenia that are not ameliorated by available drugs. In moving beyond the focus on psychotic symptoms to the cognitive symptoms of schizophrenia, animal models that do not involve manipulations of dopamine D2 receptors but that do utilize information processing measures that are correlated with cognitive disturbances are receiving increased attention. Here, selected examples of how cross-species measures of psychiatric disorders are developed and validated are discussed. Specific animal paradigms that parallel the specific domains of cognition that are altered in schizophrenia provide one focus of the review. Another focus includes efforts to develop new human models of psychiatric symptoms that are designed to parallel existing tests used in rodents.

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

  • Braff DL and MA Geyer (1990) Sensorimotor gating and schizophrenia: human and animal model studies.Arch. Gen. Psychiatry 47, 181–188.

    PubMed  CAS  Google Scholar 

  • Braff DL, MA Geyer and NR Swerdlow (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.Psychopharmacology 156, 234–258.

    Article  PubMed  CAS  Google Scholar 

  • Callaway CW, LL Wing and MA Geyer (1990) Serotonin release contributes to the locomotor stimulant effects of 3,4-methylenedioxymethamphetamine (MDMA) in rats.J. Pharmacol. Exp. Ther. 254, 456–464.

    PubMed  CAS  Google Scholar 

  • Cilia J, PD Hatcher, C Reavill and DNC Jones (2005) Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats: an update.Psychopharmacology 180, 57–62.

    Article  PubMed  CAS  Google Scholar 

  • Cryan JF and DA Slattery (2007) Animal models of mood disorders: recent developments.Curr. Opin. Psychiatry 20, 1–7.

    Article  PubMed  Google Scholar 

  • Csomor PA, RR Stadler, J Feldon, BK Yee, MA Geyer and FX Vollenweider (2008) Haloperidol differentially modulates prepulse inhibition and P50 suppression in healthy humans stratified for low and high gating levels.Neuropsychopharmacology 33, 497–512.

    Article  PubMed  CAS  Google Scholar 

  • Drai D and I Golani (2001) SEE: a tool for the visualization and analysis of rodent exploratory behavior.Neurosci. Biobehav. Rev. 25, 409–426.

    Article  PubMed  CAS  Google Scholar 

  • Eilam D, R Zor, H Szechtman and H Hermesh (2006) Rituals, stereotypy and compulsive behavior in animals and humans.Neurosci. Biobehav. Rev. 30, 456–471.

    Article  PubMed  Google Scholar 

  • Einat H (2006) Modelling facets of mania — new directions related to the notion of endophenotypes.J. Psychopharmacology (Oxford, England)20, 714–722.

    Article  Google Scholar 

  • Feifel D, G Melendez, K Priebe, PD Shilling (2007) The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats.Behav. Brain Res. 181, 278–86.

    Article  PubMed  CAS  Google Scholar 

  • Fenton WS, EL Stover and TR Insel (2003) Breaking the logjam in treatment development for cognition in schizophrenia.Psychopharmacology 169, 365–366.

    Article  PubMed  CAS  Google Scholar 

  • Floresco S, MA Geyer, LH Gold and A Grace (2005) Developing predictive animal models and establishing a preclinical trials network for assessing treatment effects on cognition in schizophrenia.Schizophr. Bull. 31, 888–894.

    Article  PubMed  Google Scholar 

  • Freedman R, LE Adler and S Leonard (1999) Alternative phenotypes for the complex genetics of schizophrenia.Biol. Psychiatry 45, 551–558.

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA (2006) Are cross-species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia?Dialogues Clin. Neurosci. 8, 9–16.

    PubMed  Google Scholar 

  • Geyer MA and BA Ellenbroek (2003) Animal behavior models of the mechanisms underlying antipsychotic atypicality. Prog. Neuropsychopharmacol.Biol. Psychiatry 27, 1071–1079.

    CAS  Google Scholar 

  • Geyer MA and M Paulus (1996) Multivariate analyses of locomotor and investigatory behavior in rodents, In:Measuring Movement and Locomotion: From Invertebrates to Humans (Ossenkopp K, M Kavaliers & PR Sanberg, Eds.) (Chapman & Hall:New York, NY).

    Google Scholar 

  • Geyer MA, PV Russo and VL Masten (1986) Multivariate assessment of locomotor behavior: pharmacological and behavioral analyses.Pharmacol. Biochem. Behav. 25, 277–288.

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, K Krebs-Thomson, DL Braff and NR Swerdlow (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.Psychopharmacology 156, 117–154.

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, KL McIlwain and R Paylor (2002) Mouse genetic models for prepulse inhibition: an early review.Mol. Psychiatry 7, 1039–1053.

    Article  PubMed  CAS  Google Scholar 

  • Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia?Am. J. Psychiatry 153, 321–330.

    PubMed  CAS  Google Scholar 

  • Green MF, SR Kerns and RK Heaton (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS.Schizophr. Res. 72, 45–51.

    Google Scholar 

  • Hagan JJ and DN Jones (2005) Predicting drug efficacy for cognitive deficits in schizophrenia.Schizophr. Bull. 31, 830–853.

    Article  PubMed  Google Scholar 

  • Kincaid MJ, A Minassian, EJ Ferguson, MA Geyer, MP Paulus and W Perry (2007) Exploratory behavior differentiates patients with acute psychotic mania from schizophrenia.Biol. Psychiatry 61, 139S.

    Article  Google Scholar 

  • Kumari V, W Soni and T Sharma (1999) Normalization of information processing deficits in schizophrenia with clozapine.Am. J. Psychiatry 156, 1046–1051.

    PubMed  CAS  Google Scholar 

  • Ludewig K, MA Geyer and FX Vollenweider (2003) Deficits in prepulse inhibition and habituation in never-medicated firstepisode schizophrenia.Biol. Psychiatry 54, 121–128.

    Article  PubMed  Google Scholar 

  • Marder SR and W Fenton (2004) Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia.Schizophr. Res. 72, 5–9.

    Article  PubMed  Google Scholar 

  • Martin LF, WR Kem and R Freedman (2004) Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.Psychopharmacology 174, 54–64.

    Article  PubMed  CAS  Google Scholar 

  • Meltzer HY and SR McGurk (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.Schizophr. Bull. 25, 233–255.

    PubMed  CAS  Google Scholar 

  • Minassian A, MA Geyer, MP Paulus, EJ Ferguson, R Sharp and W Perry (2007) Quantification of motor hyperactivity in mania: the human behavioral pattern monitorBiol. Psychiatry 61, 222S.

    Google Scholar 

  • Nuechterlein KH, DM Barch, JM Gold, TE Goldberg, MF Green and RK Heaton (2004) Identification of separable cognitive factors in schizophrenia.Schizophr. Res. 72, 29–39.

    Article  PubMed  Google Scholar 

  • Olivier B, C Leahy, T Mullen, R Paylor, FE Groppi, Z Sarnyai and D Brunner (2001) The DBA/2J strain and prepulse inhibition of startle: a model system to test antipsychotics?Psychopharmacology 156, 284–290.

    Article  PubMed  CAS  Google Scholar 

  • Ouagazzal A-M, F Jenck and J-L Moreau (2001) Drug-induced potentiation of prepulse inhibition of acoustic startle reflex in mice: a model for detecting antipsychotic activity.Psychopharmacology 156, 273–283.

    Article  PubMed  CAS  Google Scholar 

  • Palmer AA, SC Dulawa, AA Mottiwala, LH Conti, MA Geyer and MP Printz (2000) Prepulse startle deficit in the Brown-Norway rat. A potential genetic model.Behav. Neurosci. 114, 374–388.

    Article  PubMed  CAS  Google Scholar 

  • Paulus MP, A Minassian, V Masten, D Feifel, MA Geyer and W Perry (2007) Human behavioral pattern monitor differentiates activity patterns of bipolar manic and attention deficit hyperactivity subjects.Biol. Psychiatry 61, 227S.

    Google Scholar 

  • Perry W, A Minassian, D Feifel and DL Braff (2001) Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania.Biol. Psychiatry 50, 418–424.

    Article  PubMed  CAS  Google Scholar 

  • Powell SB and MA Geyer (2002) Developmental markers of psychiatric disorders as identified by sensorimotor gating.Neurotox. Res. 4, 489–502.

    Article  PubMed  Google Scholar 

  • Risbrough VB, VL Masten, S Caldwell, MP Paulus, MJ Low and MA Geyer (2006) Differential contributions of dopamine D(1), D(2), and D(3) receptors to MDMA-induced effects on locomotor behavior patterns in mice.Neuropsychopharmacology 31, 2349–2358.

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR and MA Geyer (1993) Clozapine and haloperidol in an animal model of sensorimotor gating deficits in schizophrenia.Pharmacol. Biochem. Behav. 44, 741–744.

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, MA Geyer and DL Braff (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges.Psychopharmacology 156, 194–215.

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, J Talledo, AN Sutherland, D Nagy and JM Shoemaker (2006) Antipsychotic effects on prepulse inhibition in normal ‘low gating’ humans and rats.Neuropsychopharmacology 31, 2011–2021.

    Article  PubMed  CAS  Google Scholar 

  • Vollenweider FX, M Barro, PA Csomor and J Feldon (2006) Clozapine enhances prepulse inhibition in healthy humans with low but not with high prepulse inhibition levels.Biol. Psychiatry 60, 597–603.

    Article  PubMed  CAS  Google Scholar 

  • Young, J, MA Geyer, and the TURNS Preclinical Subcommittee (2006) Cognitive task list and preclinical task survey. http://www.turns.ucla.edu/preclinical-TURNS-report-2006b.pdf

  • Young JW, A Minassian, MP Paulus, MA Geyer and W Perry (2007a) A reverse-translational approach to bipolar disorder: rodent and human studies in the behavioral pattern monitor.Neurosci. Biobehav. Rev. 31, 882–896.

    Article  PubMed  Google Scholar 

  • Young JW, AKL Goey, VL Masten, R Sharp, MP Paulus, W Perry and MA Geyer (2007b) Genetic and acute pharmacological animal models of bipolar disorder mania: mimicking recent insights of disordered movement and exploration.Biol. Psychiatry 61, 38S.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, 92093-0804, La Jolla, CA, USA

    Mark A. Geyer

Authors
  1. Mark A. Geyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark A. Geyer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Geyer, M.A. Developing translational animal models for symptoms of schizophrenia or bipolar mania. neurotox res 14, 71–78 (2008). https://doi.org/10.1007/BF03033576

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033576

Keywords

Search

Navigation