Overview of Animal Models of Schizophrenia

Susan B. Powell1, Mark A. Geyer1

1 University of California, San Diego, La Jolla, California
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.24
DOI:  10.1002/0471142301.ns0924s39
Online Posting Date:  April, 2007
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Abstract

Animal models of schizophrenia may increase the understanding of the neurological abnormalities associated with the disorder and aid in the development of rational pharmacological treatments. Rather than attempting to model the entire syndrome of schizophrenia, a more biologically oriented approach to animal models has been to focus on specific symptoms of schizophrenia that are more objectively measured in the clinical population and more directly translatable to animals (e.g., observables or endophenotypes). This overview focuses on behavioral measures that have been investigated in rodent models of schizophrenia with varying degrees of predictive, etiological, and construct validity. Because of the severity of cognitive deficits in schizophrenia and their resistance to current treatments, there is a need to develop animal models specific to the cognitive symptoms of schizophrenia. In light of this need, this overview discusses rodent models of cognition with relevance to the core cognitive deficits observed in schizophrenia.

Keywords: animal model; schizophrenia; cognition; validity; antipsychotic; rodent

     
 
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Table of Contents

  • Animal Models
  • Measures Used to Assess Cognitive Changes Relevant to Schizophrenia
  • Conclusions
  • Literature Cited
     
 
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Materials

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Literature Cited

Literature Cited
   Addington, J., Addington, D., and Gasbarre, L. 1997. Distractibility and symptoms in schizophrenia. J. Psychiatry Neurosci. 22:180‐184.
   Aguado, L., San Antonio, A., Perez, L., del Valle, R., and Gomez, J. 1994. Effects of the NMDA receptor antagonist ketamine on flavor memory: Conditioned aversion, latent inhibition, and habituation of neophobia. Behav. Neural. Biol. 61:271‐281.
   Arnold, S.E., Hyman, B.T., Van Hoesen, G.W., and Damasio, A.R. 1991. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. Arch. Gen. Psychiatry 48:625‐632.
   Aultman, J.M. and Moghaddam, B. 2001. Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Psychopharmacology (Berl) 153:353‐364.
   Awh, E., Vogel, E.K., and Oh, S.H. 2006. Interactions between attention and working memory. Neuroscience 139:201‐208.
   Baddeley, A. 1981. The concept of working memory: A view of its current state and probable future development. Cognition 10:17‐23.
   Baddeley, A. 1996. The fractionation of working memory. Proc. Natl. Acad. Sci. U.S.A. 93:13468‐13472.
   Baddeley, A. 2000. The episodic buffer: A new component of working memory? Trends Cogn. Sci. 4:417‐423.
   Baddeley, A. and Salame, P. 1986. The unattended speech effect: Perception or memory? J. Exp. Psychol. Learn Mem. Cogn. 12:525‐529.
   Barnes, C.A. 1979. Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat. J. Comp. Physiol. Psychol. 93:74‐104.
   Barrett, S.L., Bell, R., Watson, D., and King, D.J. 2004. Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers. J. Psychopharmacol. 18:156‐172.
   Becker, J., Gomes, I., Ghisolfi, E.S., Schuch, A., Ramos, F.L., Ehlers, J.A., Nora, D.B., Lara, D.R., and da Costa, J.C. 2004. Clozapine, but not typical antipsychotics, correct P50 suppression deficit in patients with schizophrenia. Clin. Neurophysiol. 115:396‐401.
   Bianchi, M., Fone, K.F., Azmi, N., Heidbreder, C.A., Hagan, J.J., and Marsden, C.A. 2006. Isolation rearing induces recognition memory deficits accompanied by cytoskeletal alterations in rat hippocampus. Eur. J. Neurosci. 24:2894‐2902.
   Birrell, J.M. and Brown, V.J. 2000. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J. Neurosci. 20:4320‐4324.
   Bolino, F., Di Michele, V., Di Cicco, L., Manna, V., Daneluzzo, E., and Casacchia, M. 1994. Sensorimotor gating and habituation evoked by electro‐cutaneous stimulation in schizophrenia. Biol. Psychiatry. 36:670‐679.
   Bontempi, B., Whelan, K.T., Risbrough, V.B., Rao, T.S., Buccafusco, J.J., Lloyd, G.K., and Menzaghi, F. 2001. SIB‐1553A, (+/−)‐4‐[[2‐(1‐methyl‐2‐pyrrolidinyl)ethyl]thio]phenol hydrochloride, a subtype‐selective ligand for nicotinic acetylcholine receptors with putative cognitive‐enhancing properties: Effects on working and reference memory performances in aged rodents and nonhuman primates. J. Pharmacol. Exp. Ther. 299:297‐306.
   Bontempi, B., Whelan, K.T., Risbrough, V.B., Lloyd, G.K., and Menzaghi, F. 2003. Cognitive enhancing properties and tolerability of cholinergic agents in mice: A comparative study of nicotine, donepezil, and SIB‐1553A, a subtype‐selective ligand for nicotinic acetylcholine receptors. Neuropsychopharmacology 28:1235‐1246.
   Borrell, J., Vela, J.M., Arevalo‐Martin, A., Molina‐Holgado, E., and Guaza, C. 2002. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology 26:204‐215.
   Bowers, M.B., Jr. and Freedman, D.X. 1966. “Psychedelic” experiences in acute psychoses. Arch. Gen. Psychiatry 15:240‐248.
   Braff, D.L. and Geyer, M.A. 1990. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch. Gen. Psychiatry 47:181‐188.
   Braff, D.L., Geyer, M.A., and Swerdlow, N.R. 2001. Human studies of prepulse inhibition of startle: Normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156:234‐258.
   Brito, G.N. and Thomas, G.J. 1981. T‐maze alternation, response patterning, and septo‐hippocampal circuitry in rats. Behav. Brain Res. 3:319‐340.
   Brito, G.N., Thomas, G.J., Davis, B.J., and Gingold, S.I. 1982. Prelimbic cortex, mediodorsal thalamus, septum, and delayed alternation in rats. Exp. Brain Res. 46:52‐58.
   Bruins Slot, L.A., Kleven, M.S., and Newman‐Tancredi, A. 2005. Effects of novel antipsychotics with mixed D(2) antagonist/5‐HT(1A) agonist properties on PCP‐induced social interaction deficits in the rat. Neuropharmacology 49:996‐1006.
   Cadenhead, K.S., Geyer, M.A., and Braff, D.L. 1993. Impaired startle prepulse inhibition and habituation in patients with schizotypal personality disorder. Am. J. Psychiatry 150:1862‐1867.
   Cadenhead, K.S., Light, G.A., Geyer, M.A., McDowell, J.E., and Braff, D.L. 2002. Neurobiological measures of schizotypal personality disorder: Defining an inhibitory endophenotype? Am. J. Psychiatry 159:869‐871.
   Carli, M., Evenden, J.L., and Robbins, T.W. 1985. Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention. Nature 313:679‐682.
   Carter, C.S., Perlstein, W., Ganguli, R., Brar, J., Mintun, M., and Cohen, J.D. 1998. Functional hypofrontality and working memory dysfunction in schizophrenia. Am. J. Psychiatry 155:1285‐1287.
   Castner, S.A., Goldman‐Rakic, P.S., and Williams, G.V. 2004. Animal models of working memory: Insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology (Berl) 174:111‐125.
   Cho, Y.H., Beracochea, D., and Jaffard, R. 1992. Differential effects of ibotenate lesions of the CA1 subfield of the hippocampus on a delayed‐matching‐to‐place task as a function of preoperative training in mice. Psychobiology 20:261‐269.
   Choi, K.H. and Kwon, J.H. 2006. Social cognition enhancement training for schizophrenia: A preliminary randomized controlled trial. Community Ment. Health J. 42:177‐187.
   Chudasama, Y. and Muir, J.L. 1997. A behavioural analysis of the delayed non‐matching to position task: The effects of scopolamine, lesions of the fornix and of the prelimbic region on mediating behaviours by rats. Psychopharmacology (Berl) 134:73‐82.
   Chudasama, Y. and Robbins, T.W. 2004. Psychopharmacological approaches to modulating attention in the five‐choice serial reaction time task: Implications for schizophrenia. Psychopharmacology (Berl) 174:86‐98.
   Chudasama, Y., Passetti, F., Rhodes, S.E., Lopian, D., Desai, A., and Robbins, T.W. 2003. Dissociable aspects of performance on the 5‐choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: Differential effects on selectivity, impulsivity and compulsivity. Behav. Brain Res. 146:105‐119.
   Cilia, J., Hatcher, P.D., Reavill, C., and Jones, D.N. 2005. Long‐term evaluation of isolation‐rearing induced prepulse inhibition deficits in rats: An update. Psychopharmacology (Berl) 180:57‐62.
   Corrigan, P.W. and Addis, I.B. 1995. Effects of extraneous stimuli on social cue perception in schizophrenia. Psychiatry Res. 56:111‐120.
   Courtiere, A., Hardouin, J., Hasbroucq, T., Possamai, C., and Vidal, F. 2000. The additive factor method in rat information processing. Behav Processes 50:113‐121.
   Creese, I. 1983. Stimulants: Neurochemical, Behavioral, and Clinical Perspectives. Raven, New York.
   Cronbach, L.J. and Meehl, P.E. 1955. Construct validity in psychological tests. Psychol. Bull. 52:281‐302.
   Dantzer, R., Bluthe, R.M., and LeMoal, M. 1988. Experimental assessment of drug‐induced changes in cognitive function: Vasopressin as a case study. Neurotoxicology 9:471‐477.
   de Bruin, N.M., van Luijtelaar, E.L., Cools, A.R., and Ellenbroek, B.A. 2001. Auditory information processing in rat genotypes with different dopaminergic properties. Psychopharmacology (Berl) 156:352‐359.
   Dias, R., Robbins, T.W., and Roberts, A.C. 1996. Dissociation in prefrontal cortex of affective and attentional shifts. Nature 380:69‐72.
   Dobrossy, M.D. and Dunnett, S.B. 1998. Striatal grafts alleviate deficits in response execution in a lateralised reaction time task. Brain Res. Bull. 47:585‐593.
   Dudchenko, P.A. 2004. An overview of the tasks used to test working memory in rodents. Neurosci. Biobehav. Rev. 28:699‐709.
   Dunnett, S.B. 1985. Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria‐fornix on delayed matching in rats. Psychopharmacology (Berl) 87:357‐363.
   El‐Khodor, B.F. and Boksa, P. 1998. Birth insult increases amphetamine‐induced behavioral responses in the adult rat. Neuroscience 87:893‐904.
   Ellenbroek, B.A. and Cools, A.R. 1990. Animal models with construct validity for schizophrenia. Behav. Pharmacol. 1:469‐490.
   Ellenbroek, B.A. and Cools, A.R. 1995. Animal models of psychotic disturbances. In Advances in the Neurobiology of Schizophrenia. (J.A. den Beor, H.G.M. Westenberg, H.M. van Praag, eds.) pp. 89‐109. John Wiley & Sons Ltd., Chichester.
   Ellenbroek, B.A., Geyer, M.A., and Cools, A.R. 1995. The behavior of APO‐SUS rats in animal models with construct validity for schizophrenia. J. Neurosci. 15:7604‐7611.
   Embretson (Whitely), S. 1983. Construct validity: Construct representation versus nomothetic span. Psychol. Bull. 93:179‐197.
   Engelmann, M., Wotjak, C.T., and Landgraf, R. 1995. Social discrimination procedure: An alternative method to investigate juvenile recognition abilities in rats. Physiol. Behav. 58:315‐321.
   Ennaceur, A. and Delacour, J. 1988. A new one‐trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav. Brain Res. 31:47‐59.
   Feldon, J., Shofel, A., and Weiner, I. 1991. Latent inhibition is unaffected by direct dopamine agonists. Pharmacol. Biochem. Behav. 38:309‐314.
   Ferguson, J.N., Young, L.J., and Insel, T.R. 2002. The neuroendocrine basis of social recognition. Front Neuroendocrinol 23:200‐224.
   Fletcher, P.J., Tenn, C.C., Rizos, Z., Lovic, V., and Kapur, S. 2005. Sensitization to amphetamine, but not PCP, impairs attentional set shifting: Reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Psychopharmacology (Berl) 183:190‐200.
   Flores, G., Silva‐Gomez, A.B., Ibanez, O., Quirion, R., and Srivastava, L.K. 2005. Comparative behavioral changes in postpubertal rats after neonatal excitotoxic lesions of the ventral hippocampus and the prefrontal cortex. Synapse 56:147‐153.
   Freedman, R., Adler, L.E., and Leonard, S. 1999. Alternative phenotypes for the complex genetics of schizophrenia. Biol. Psychiatry 45:551‐558.
   Freeman, J.H., Jr. and Stanton, M.E. 1991. Fimbria‐fornix transections disrupt the ontogeny of delayed alternation but not position discrimination in the rat. Behav. Neurosci. 105:386‐395.
   Frielingsdorf, H., Thal, L.J., and Pizzo, D.P. 2006. The septohippocampal cholinergic system and spatial working memory in the Morris water maze. Behav. Brain Res. 168:37‐46.
   Gevins, A.S., Bressler, S.L., Cutillo, B.A., Illes, J., Miller, J.C., Stern, J., and Jex, H.R. 1990. Effects of prolonged mental work on functional brain topography. Electroencephalogr. Clin. Neurophysiol. 76:339‐350.
   Geyer, M.A. 2006. Are cross‐species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia? Dialogues Clin. Neurosci. 8:9‐16.
   Geyer, M.A. and Braff, D.L. 1982. Habituation of the Blink reflex in normals and schizophrenic patients. Psychophysiology 19:1‐6.
   Geyer, M.A. and Ellenbroek, B. 2003. Animal behavior models of the mechanisms underlying antipsychotic atypicality. Prog. Neuropsychopharmacol. Biol. Psychiatry 27:1071‐1079.
   Geyer, M.A. and Heinssen, R. 2005. New approaches to measurement and treatment research to improve cognition in schizophrenia. Schizophr. Bull. 31:806‐809.
   Geyer, M.A. and Markou, A. 1995. Animal models of psychiatric disorders. In Psychopharmacology: The Fourth Generation of Progress. (F.E. Bloom and D. Kupfer, eds.) pp. 787‐798. Raven Press, New York.
   Geyer, M.A. and Markou, A. 2000. Animal models of psychiatric disorders. In Psychopharmacology: The Fourth Generation of Progress CD‐ROM Version 3. (S. Watson, ed.) Lippincott Williams & Wilkins.
   Geyer, M.A. and Markou, A. 2002. The role of preclinical models in the development of psychotropic drugs. In Neuropsychopharmacology: The Fifth Generation of Progress. (K.L. Davis, D. Charney, J.T. Coyle, and C.B. Nemeroff, eds.) pp. 445‐455. Lippincott, Williams & Wilkins.
   Geyer, M.A. and Moghaddam, B. 2000. Animal models relevant to schizophrenia disorders. In Neuropsychopharmacology: The Fifth Generation of Progress. (K.L. Davis, D. Charney, J.T. Coyle, and C.B. Nemeroff, eds.) pp. 689‐701. Lippincott Williams & Wilkins.
   Geyer, M.A. and Tapson, G.S. 1988. Habituation of tactile startle is altered by drugs acting on serotonin‐2 receptors. Neuropsychopharmacology 1:135‐147.
   Geyer, M.A., Swerdlow, N.R., Mansbach, R.S., and Braff, D.L. 1990. Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res. Bull. 25:485‐498.
   Geyer, M.A., Wilkinson, L.S., Humby, T., and Robbins, T.W. 1993. Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia. Biol. Psychiatry 34:361‐372.
   Geyer, M.A., Krebs‐Thomson, K., Braff, D.L., and Swerdlow, N.R. 2001. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: A decade in review. Psychopharmacology (Berl) 156:117‐154.
   Goldberg, T.E., Saint‐Cyr, J.A., and Weinberger, D.R. 1990. Assessment of procedural learning and problem solving in schizophrenic patients by Tower of Hanoi type tasks. J. Neuropsychiatry Clin. Neurosci. 2:165‐173.
   Goldberg, T.E., Bigelow, L.B., Weinberger, D.R., Daniel, D.G., and Kleinman, J.E. 1991. Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia. Am. J. Psychiatry 148:78‐84.
   Goldman‐Rakic, P.S. 1990. Cellular and circuit basis of working memory in prefrontal cortex of nonhuman primates. Prog. Brain Res. 85:325‐335; discussion 335‐326.
   Goldman‐Rakic, P.S. 1994. Working memory dysfunction in schizophrenia. J. Neuropsychiatry Clin. Neurosci. 6:348‐357.
   Goosen, C. 1981. Abnormal behavior patterns in rhesus monkeys: Symptoms of mental disease. Biol. Psychiatry 16:697‐716.
   Gottesman, I.I. 1991. Schizophrenia Genesis. W.H. Freeman, New York.
   Gould, T.D. and Gottesman, II. 2006. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav. 5:113‐119.
   Gouzoulis‐Mayfrank, E., Habermeyer, E., Hermle, L., Steinmeyer, A.M., Kunert, H.J., and Sass, H. 1998. Hallucinogenic drug induced states resemble acute endogenous psychoses: Results of an empirical study. European Psychiatry 13:399‐406.
   Gray, N.S., Pilowsky, L.S., Gray, J.A., and Kerwin, R.W. 1995. Latent inhibition in drug naive schizophrenics: Relationship to duration of illness and dopamine D2 binding using SPET. Schizophr. Res. 17:95‐107.
   Green, M.F., Nuechterlein, K.H., Gold, J.M., Barch, D.M., Cohen, J., Essock, S., Fenton, W.S., Frese, F., Goldberg, T.E., Heaton, R.K., Keefe, R.S., Kern, R.S., Kraemer, H., Stover, E., Weinberger, D.R., Zalcman, S., and Marder, S.R. 2004. Approaching a consensus cognitive battery for clinical trials in schizophrenia: The NIMH‐MATRICS conference to select cognitive domains and test criteria. Biol. Psychiatry 56:301‐307.
   Green, R.J. and Stanton, M.E. 1989. Differential ontogeny of working memory and reference memory in the rat. Behav. Neurosci. 103:98‐105.
   Grottick, A.J. and Higgins, G.A. 2000. Effect of subtype selective nicotinic compounds on attention as assessed by the five‐choice serial reaction time task. Behav. Brain Res. 117:197‐208.
   Hagan, J.J. and Jones, D.N. 2005. Predicting drug efficacy for cognitive deficits in schizophrenia. Schizophr. Bull. 31:830‐853.
   Hammond, R.S., Tull, L.E., and Stackman, R.W. 2004. On the delay‐dependent involvement of the hippocampus in object recognition memory. Neurobiol. Learn Mem. 82:26‐34.
   Harrison, P.J. and Owen, M.J. 2003. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361:417‐419.
   Harrison, P.J. and Weinberger, D.R. 2005. Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Mol. Psychiatry 10:40‐68.
   Heaton, R. 1985. Psychological Assessment Resources, Odessa, TX.
   Herremans, A.H. and Hijzen, T.H. 1997. The delayed‐conditional‐discrimination task improves measurement of working memory in rats. Neurosci. Biobehav. Rev. 21:371‐379.
   Hlinak, Z. and Krejci, I. 1994. Effects of excitatory amino acid antagonists on social recognition of male rats. Behav. Pharmacol. 5:239‐244.
   Hodges, H. 1996. Maze procedures: The radial‐arm and water maze compared. Brain Res. Cogn. Brain Res. 3:167‐181.
   Hodges, H., Sowinski, P., Sinden, J.D., Netto, C.A., and Fletcher, A. 1995. The selective 5‐HT3 receptor antagonist, WAY100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system. Psychopharmacology (Berl) 117:318‐332.
   Hoff, A.L., Faustman, W.O., Wieneke, M., Espinoza, S., Costa, M., Wolkowitz, O., and Csernansky, J.G. 1996. The effects of clozapine on symptom reduction, neurocognitive function, and clinical management in treatment‐refractory state hospital schizophrenic inpatients. Neuropsychopharmacology 15:361‐369.
   Holmes, A., Wrenn, C.C., Harris, A.P., Thayer, K.E., and Crawley, J.N. 2002. Behavioral profiles of inbred strains on novel olfactory, spatial and emotional tests for reference memory in mice. Genes Brain Behav. 1:55‐69.
   Holzman, P.S. and Matthysse, S. 1990. The genetics of schizophrenia: A review. Psychological Science 1:279‐286.
   Johnstone, E.C., Ebmeier, K.P., Miller, P., Owens, D.G., and Lawrie, S.M. 2005. Predicting schizophrenia: Findings from the Edinburgh high‐risk study. Br. J. Psychiatry 186:18‐25.
   Jones, G.H., Marsden, C.A., and Robbins, T.W. 1990. Increased sensitivity to amphetamine and reward‐related stimuli following social isolation in rats: possible disruption of dopamine‐dependent mechanisms of the nucleus accumbens. Psychopharmacology (Berl) 102:364‐372.
   Jones, G.H., Hernandez, T.D., Kendall, D.A., Marsden, C.A., and Robbins, T.W. 1992. Dopaminergic and serotonergic function following isolation rearing in rats: Study of behavioural responses and postmortem and in vivo neurochemistry. Pharmacol. Biochem. Behav. 43:17‐35.
   Joober, R., Zarate, J.M., Rouleau, G.A., Skamene, E., and Boksa, P. 2002. Provisional mapping of quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle. Neuropsychopharmacology 27:765‐781.
   Keefe, R.S., Silva, S.G., Perkins, D.O., and Lieberman, J.A. 1999. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: A review and meta‐analysis. Schizophr. Bull. 25:201‐222.
   Krystal, J.H., Karper, L.P., Seibyl, J.P., Freeman, G.K., Delaney, R., Bremner, J.D., Heninger, G.R., Bowers, M.B., Jr., and Charney, D.S. 1994. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51:199‐214.
   Kumari, V. and Sharma, T. 2002. Effects of typical and atypical antipsychotics on prepulse inhibition in schizophrenia: A critical evaluation of current evidence and directions for future research. Psychopharmacology (Berl) 162:97‐101.
   Laviola, G., Adriani, W., Rea, M., Aloe, L., and Alleva, E. 2004. Social withdrawal, neophobia, and stereotyped behavior in developing rats exposed to neonatal asphyxia. Psychopharmacology (Berl) 175:196‐205.
   Le Pen, G., Grottick, A.J., Higgins, G.A., Martin, J.R., Jenck, F., and Moreau, J.L. 2000. Spatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: Further evaluation of an animal model of schizophrenia. Behav. Pharmacol. 11:257‐268.
   Le Pen, G. and Moreau, J.L. 2002. Disruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophrenia: Reversal by clozapine, olanzapine and risperidone but not by haloperidol. Neuropsychopharmacology 27:1‐11.
   Le Pen, G., Kew, J., Alberati, D., Borroni, E., Heitz, M.P., and Moreau, J.L. 2003. Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal‐lesioned rats: Reversal by glycine and a glycine transporter inhibitor. Biol. Psychiatry 54:1162‐1170.
   Lim, M.M., Bielsky, I.F., and Young, L.J. 2005. Neuropeptides and the social brain: Potential rodent models of autism. Int. J. Dev. Neurosci. 23:235‐243.
   Lipska, B.K. and Weinberger, D.R. 1993. Delayed effects of neonatal hippocampal damage on haloperidol‐induced catalepsy and apomorphine‐induced stereotypic behaviors in the rat. Brain Res. Dev. Brain Res. 75:213‐222.
   Lipska, B.K. and Weinberger, D.R. 2000. To model a psychiatric disorder in animals: Schizophrenia as a reality test. Neuropsychopharmacology 23:223‐239.
   Lipska, B.K., Jaskiw, G.E., and Weinberger, D.R. 1993. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: A potential animal model of schizophrenia. Neuropsychopharmacology 9:67‐75.
   Lipska, B.K., Swerdlow, N.R., Geyer, M.A., Jaskiw, G.E., Braff, D.L., and Weinberger, D.R. 1995. Neonatal excitotoxic hippocampal damage in rats causes post‐pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology (Berl) 122:35‐43.
   Lipska, B.K., Aultman, J.M., Verma, A., Weinberger, D.R., and Moghaddam, B. 2002. Neonatal damage of the ventral hippocampus impairs working memory in the rat. Neuropsychopharmacology 27:47‐54.
   Ludewig, S., Geyer, M.A., Ramseier, M., Vollenweider, F.X., Rechsteiner, E., and Cattapan‐Ludewig, K. 2005. Information‐processing deficits and cognitive dysfunction in panic disorder. J. Psychiatry Neurosci. 30:37‐43.
   Mandal, M.K., Pandey, R., and Prasad, A.B. 1998. Facial expressions of emotions and schizophrenia: A review. Schizophr. Bull. 24:399‐412.
   Markowska, A., Buresova, O., and Bures, J. 1983. An attempt to account for controversial estimates of working memory persistence in the radial maze. Behav. Neural. Biol. 38:97‐112.
   Martin, L.F., Kem, W.R., and Freedman, R. 2004. Alpha‐7 nicotinic receptor agonists: Potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl) 174:54‐64.
   Matthysse, S. 1986. Animal models in psychiatric research. Prog. Brain Res. 65:259‐270.
   McAlonan, G.M., Daly, E., Kumari, V., Critchley, H.D., van Amelsvoort, T., Suckling, J., Simmons, A., Sigmundsson, T., Greenwood, K., Russell, A., Schmitz, N., Happe, F., Howlin, P., and Murphy, D.G. 2002. Brain anatomy and sensorimotor gating in Asperger's syndrome. Brain 125:1594‐1606.
   McCartan, D., Bell, R., Green, J.F., Campbell, C., Trimble, K., Pickering, A., and King, D.J. 2001. The differential effects of chlorpromazine and haloperidol on latent inhibition in healthy volunteers. J. Psychopharmacol. 15:96‐104.
   McClellan, J., Breiger, D., McCurry, C., and Hlastala, S.A. 2003. Premorbid functioning in early‐onset psychotic disorders. J. Am. Acad. Child Adolesc. Psychiatry 42:666‐672.
   McGhie, A. and Chapman, J. 1961. Disorders of attention and perception in early schizophrenia. Br. J. Med. Psychol. 34:103‐116.
   Means, L.W., Long, M., Jones, T.A., and Curtis, W.C. 1996. Rats perform better on spatial than brightness delayed matching‐to‐sample water‐escape due to an unlearned bias to use spatial cues. Physiol. Behav. 60:1239‐1245.
   Mednick, S.A., Machon, R.A., Huttunen, M.O., and Bonett, D. 1988. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch. Gen. Psychiatry 45:189‐192.
   Meltzer, H.Y. and McGurk, S.R. 1999. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr. Bull. 25:233‐255.
   Meyer, U., Feldon, J., Schedlowski, M., and Yee, B.K. 2005. Towards an immuno‐precipitated neurodevelopmental animal model of schizophrenia. Neurosci. Biobehav. Rev. 29:913‐947.
   Miller, P., Byrne, M., Hodges, A., Lawrie, S.M., Owens, D.G., and Johnstone, E.C. 2002. Schizotypal components in people at high risk of developing schizophrenia: Early findings from the Edinburgh high‐risk study. Br. J. Psychiatry 180:179‐184.
   Mohn, A.R., Gainetdinov, R.R., Caron, M.G., and Koller, B.H. 1999. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98:427‐436.
   Morris, R. 1984. Developments of a water‐maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11:47‐60.
   Morris, R.G., Garrud, P., Rawlins, J.N., and O'Keefe, J. 1982. Place navigation impaired in rats with hippocampal lesions. Nature 297:681‐683.
   Mosier, C.I. 1947. A critical examination of the concepts of face validity. Educational and Psychological Measurement 7:191‐205.
   Nagahama, Y., Okada, T., Katsumi, Y., Hayashi, T., Yamauchi, H., Oyanagi, C., Konishi, J., Fukuyama, H., and Shibasaki, H. 2001. Dissociable mechanisms of attentional control within the human prefrontal cortex. Cereb. Cortex 11:85‐92.
   Nagamoto, H.T., Adler, L.E., Hea, R.A., Griffith, J.M., McRae, K.A., and Freedman, R. 1996. Gating of auditory P50 in schizophrenics: Unique effects of clozapine. Biol. Psychiatry 40:181‐188.
   Nestor, P.G. and O'Donnell, B.F. 1998. The mind adrift: Attentional dysregulation in schizophrenia. In The Attentive Brain. (R. Parasuraman, ed.) pp. 527‐546. MIT Press, Cambridge, Mass.
   Nuechterlein, K.H., Barch, D.M., Gold, J.M., Goldberg, T.E., Green, M.F., and Heaton, R.K. 2004. Identification of separable cognitive factors in schizophrenia. Schizophr. Res. 72:29‐39.
   O'Callaghan, E., Sham, P., Takei, N., Glover, G., and Murray, R.M. 1991. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet. 337:1248‐1250.
   Oranje, B., van Berckel, B.N., Kemner, C., van Ree, J.M., Kahn, R.S., and Verbaten, M.N. 1999. P50 suppression and prepulse inhibition of the startle reflex in humans: A correlational study. Biol. Psychiatry 45:883‐890.
   Oranje, B., Geyer, M.A., Bocker, K.B., Leon Kenemans, J., and Verbaten, M.N. 2006. Prepulse inhibition and P50 suppression: Commonalities and dissociations. Psychiatry Res. 143:147‐158.
   Orzack, M.H. and Kornetsky, C. 1966. Attention dysfunction in chronic schizophrenia. Arch. Gen. Psychiatry 14:323‐326.
   Owen, M.J. and Lewis, S.W. 1986. Lateral ventricular size in schizophrenia. Lancet 2:223‐224.
   Ozawa, K., Hashimoto, K., Kishimoto, T., Shimizu, E., Ishikura, H., and Iyo, M. 2006. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: A neurodevelopmental animal model of schizophrenia. Biol. Psychiatry 59:546‐554.
   Parasuraman, R. 1998. The attentive brain: Issues and concepts. In The Attentive Brain. (R. Parasuraman, ed.) pp. 3‐15. MIT Press, Cambridge, Mass.
   Park, S., Puschel, J., Sauter, B.H., Rentsch, M., and Hell, D. 1999. Spatial working memory deficits and clinical symptoms in schizophrenia: A 4‐month follow‐up study. Biol. Psychiatry 46:392‐400.
   Park, S., Puschel, J., Sauter, B.H., Rentsch, M., and Hell, D. 2002. Spatial selective attention and inhibition in schizophrenia patients during acute psychosis and at 4‐month follow‐up. Biol. Psychiatry 51:498‐506.
   Paylor, R. and Crawley, J.N. 1997. Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology (Berl) 132:169‐180.
   Paylor, R., Zhao, Y., Libbey, M., Westphal, H., and Crawley, J.N. 2001. Learning impairments and motor dysfunctions in adult Lhx5‐deficient mice displaying hippocampal disorganization. Physiol. Behav. 73:781‐792.
   Penn, D.L., Corrigan, P.W., Bentall, R.P., Racenstein, J.M., and Newman, L. 1997. Social cognition in schizophrenia. Psychol. Bull. 121:114‐132.
   Penn, D.L., Ritchie, M., Francis, J., Combs, D., and Martin, J. 2002. Social perception in schizophrenia: The role of context. Psychiatry Res. 109:149‐159.
   Perry, W., Minassian, A., Feifel, D., and Braff, D.L. 2001. Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania. Biol. Psychiatry 50:418‐424.
   Perry, W., Minassian, A., Lopez, B., Maron, L., and Lincoln, A. 2006. Sensorimotor Gating Deficits in Adults with Autism. Biol. Psychiatry Feb 3, Epub ahead of print.
   Pontecorvo, M.J., Sahgal, A., and Steckler, T. 1996. Further developments in the measurement of working memory in rodents. Brain Res. Cogn. Brain Res. 3:205‐213.
   Potter, D., Summerfelt, A., Gold, J., and Buchanan, R.W. 2006. Review of clinical correlates of p50 sensory gating abnormalities in patients with schizophrenia. Schizophr. Bull. 32:692‐700.
   Powell, S.B. and Geyer, M.A. 2002. Developmental markers of psychiatric disorders as identified by sensorimotor gating. Neurotox. Res. 4:489‐502.
   Ragozzino, M.E., Detrick, S., and Kesner, R.P. 1999a. Involvement of the prelimbic‐infralimbic areas of the rodent prefrontal cortex in behavioral flexibility for place and response learning. J. Neurosci. 19:4585‐4594.
   Ragozzino, M.E., Wilcox, C., Raso, M., and Kesner, R.P. 1999b. Involvement of rodent prefrontal cortex subregions in strategy switching. Behav. Neurosci. 113:32‐41.
   Reitan, R.M. 1979. Neuropsychology Laboratory. University of Arizona, Tuscon, AZ.
   Repovs, G. and Baddeley, A. 2006. The multi‐component model of working memory: Explorations in experimental cognitive psychology. Neuroscience 139:5‐21.
   Robbins, T.W. 2002. The 5‐choice serial reaction time task: Behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163:362‐380.
   Robbins, T.W. 2005. Synthesizing schizophrenia: A bottom‐up, symptomatic approach. Schizophr. Bull. 31:854‐864.
   Rung, J.P., Carlsson, A., Ryden Markinhuhta, K., and Carlsson, M.L. 2005. (+)‐MK‐801 induced social withdrawal in rats: A model for negative symptoms of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 29:827‐832.
   Sahakian, B.J., Robbins, T.W., Morgan, M.J., and Iversen, S.D. 1975. The effects of psychomotor stimulants on stereotypy and locomotor activity in socially‐deprived and control rats. Brain Res. 84:195‐205.
   Sams‐Dodd, F. 1996. Phencyclidine‐induced stereotyped behaviour and social isolation in rats: A possible animal model of schizophrenia. Behav. Pharmacol. 7:3‐23.
   Sams‐Dodd, F. 1998. A test of the predictive validity of animal models of schizophrenia based on phencyclidine and D‐amphetamine. Neuropsychopharmacology 18:293‐304.
   Sams‐Dodd, F., Lipska, B.K., and Weinberger, D.R. 1997. Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology (Berl) 132:303‐310.
   Schwarzkopf, S.B., Lamberti, J.S., and Smith, D.A. 1993. Concurrent assessment of acoustic startle and auditory P50 evoked potential measures of sensory inhibition. Biol. Psychiatry 33:815‐828.
   Segal, D.S. and Geyer, M.A. 1985. Animal models of psychopathology. In Psychobiological Foundations of Clinical Psychiatry. (L.L. Judd and P.M. Groves, eds.) pp. 1‐14. J.B. Lippincott Co., Philadelphia.
   Segal, D.S., Geyer, M.A., and Schuckit, A. 1981. Stimulant‐induced psychosis: An evaluation of animal models. In Essays in Neurochemistry and Neuropharmacology. (M.B.H. Youdim, W. Lovenberg, D.F. Sharman, and J.R. Lagnado, eds.) pp. 95‐130. John Wiley & Sons, New York.
   Shi, L., Fatemi, S.H., Sidwell, R.W., and Patterson, P.H. 2003. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23:297‐302.
   Simosky, J.K., Stevens, K.E., Adler, L.E., and Freedman, R. 2003. Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl) 165:386‐396.
   Steele, R.J. and Morris, R.G. 1999. Delay‐dependent impairment of a matching‐to‐place task with chronic and intrahippocampal infusion of the NMDA‐antagonist D‐AP5. Hippocampus 9:118‐136.
   Stevens, K.E., Fuller, L.L., and Rose, G.M. 1991. Dopaminergic and noradrenergic modulation of amphetamine‐induced changes in auditory gating. Brain Res 555:91‐98.
   Stevens, K.E., Freedman, R., Collins, A.C., Hall, M., Leonard, S., Marks, M.J., and Rose, G.M. 1996. Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha‐bungarotoxin‐binding nicotinic cholinergic receptors in inbred mouse strains. Neuropsychopharmacology 15:152‐162.
   Stevens, K.E., Johnson, R.G., and Rose, G.M. 1997. Rats reared in social isolation show schizophrenia‐like changes in auditory gating. Pharmacol. Biochem. Behav. 58:1031‐1036.
   Stolerman, I.P., Mirza, N.R., Hahn, B., and Shoaib, M. 2000. Nicotine in an animal model of attention. Eur. J. Pharmacol. 393:147‐154.
   Swerdlow, N.R. and Geyer, M.A. 1998. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr. Bull. 24:285‐301.
   Swerdlow, N.R. and Koob, G.F. 1987. Dopamine, schizophrenia, mania, and depression: Toward a unified hypothesis of cortico‐striato‐pallido‐thalamic function. Behavioral and Brain Sciences 10:197‐245.
   Swerdlow, N.R., Braff, D.L., Taaid, N., and Geyer, M.A. 1994. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch. Gen. Psychiatry 51:139‐154.
   Swerdlow, N.R., Braff, D.L., Hartston, H., Perry, W., and Geyer, M.A. 1996. Latent inhibition in schizophrenia. Schizophr. Res. 20:91‐103.
   Swerdlow, N.R., Shoemaker, J.M., Platten, A., Pitcher, L., Goins, J., and Auerbach, P.P. 2004. Heritable differences in the dopaminergic regulation of sensorimotor gating. I. Apomorphine effects on startle gating in albino and hooded outbred rat strains and their F1 and N2 progeny. Psychopharmacology (Berl) 174:441‐451.
   Swerdlow, N.R., Geyer, M.A., Shoemaker, J.M., Light, G.A., Braff, D.L., Stevens, K.E., Sharp, R., Breier, M., Neary, A., and Auerbach, P.P. 2006. Convergence and divergence in the neurochemical regulation of prepulse inhibition of startle and N40 suppression in rats. Neuropsychopharmacology 31:506‐515.
   Taiminen, T., Jaaskelainen, S., Ilonen, T., Meyer, H., Karlsson, H., Lauerma, H., Leinonen, K.M., Wallenius, E., Kaljonen, A., and Salokangas, R.K. 2000. Habituation of the blink reflex in first‐episode schizophrenia, psychotic depression and non‐psychotic depression. Schizophr. Res. 44:69‐79.
   Takei, N., Lewis, S., Jones, P., Harvey, I., and Murray, R.M. 1996. Prenatal exposure to influenza and increased cerebrospinal fluid spaces in schizophrenia. Schizophr. Bull. 22:521‐534.
   Tamminga, C.A. and Holcomb, H.H. 2005. Phenotype of schizophrenia: A review and formulation. Mol. Psychiatry 10:27‐39.
   Terry, A.V., Jr., Risbrough, V.B., Buccafusco, J.J., and Menzaghi, F. 2002. Effects of (+/–)‐4‐[[2‐(1‐methyl‐2‐pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB‐1553A), a selective ligand for nicotinic acetylcholine receptors, in tests of visual attention and distractibility in rats and monkeys. J. Pharmacol. Exp. Ther. 301:284‐292.
   Thor, D.H. and Holloway, W.R. 1981. Persistence of social investigatory behavior in the male rat: Evidence for long‐term memory of initial copluatory experience. Animal Learning & Behavior 9:561‐565.
   Tunbridge, E.M., Bannerman, D.M., Sharp, T., and Harrison, P.J. 2004. Catechol‐o‐methyltransferase inhibition improves set‐shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J. Neurosci. 24:5331‐5335.
   Vaillancourt, C. and Boksa, P. 2000. Birth insult alters dopamine‐mediated behavior in a precocial species, the guinea pig. Implications for schizophrenia. Neuropsychopharmacology 23:654‐666.
   Van Meer, P. and Raber, J. 2005. Mouse behavioural analysis in systems biology. Biochem. J. 389:593‐610.
   Verma, A. and Moghaddam, B. 1996. NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: Modulation by dopamine. J. Neurosci. 16:373‐379.
   Weinberger, D.R. 1987. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44:660‐669.
   Weinberger, D.R. 1996. On the plausibility of “the neurodevelopmental hypothesis” of schizophrenia. Neuropsychopharmacology 14:1S‐11S.
   Weiner, I. and Feldon, J. 1992. Phencyclidine does not disrupt latent inhibition in rats: Implications for animal models of schizophrenia. Pharmacol. Biochem. Behav. 42:625‐631.
   Weiner, I., Lubow, R.E., and Feldon, J. 1988. Disruption of latent inhibition by acute administration of low doses of amphetamine. Pharmacol. Biochem. Behav. 30:871‐878.
   Williams, J.H., Wellman, N.A., Geaney, D.P., Cowen, P.J., Feldon, J., and Rawlins, J.N. 1996. Antipsychotic drug effects in a model of schizophrenic attentional disorder: A randomized controlled trial of the effects of haloperidol on latent inhibition in healthy people. Biol. Psychiatry 40:1135‐1143.
   Williams, J.H., Wellman, N.A., Geaney, D.P., Feldon, J., Cowen, P.J., and Rawlins, J.N. 1997. Haloperidol enhances latent inhibition in visual tasks in healthy people. Psychopharmacology (Berl) 133:262‐268.
   Wilner, P. 1986. Validation criteria for animal models of human mental disorders: Learned helplessness as a paradigm case. Prog. Neuropsychopharmacol. Biol. Psychiatry 10:677‐690.
   Winocur, G. and Hasher, L. 2004. Age and time‐of‐day effects on learning and memory in a non‐matching‐to‐sample test. Neurobiol. Aging 25:1107‐1115.
   Winslow, J.T. and Camacho, F. 1995. Cholinergic modulation of a decrement in social investigation following repeated contacts between mice. Psychopharmacology (Berl) 121:164‐172.
   Winters, B.D., Forwood, S.E., Cowell, R.A., Saksida, L.M., and Bussey, T.J. 2004. Double dissociation between the effects of peri‐postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: Heterogeneity of function within the temporal lobe. J. Neurosci. 24:5901‐5908.
   Winters, B.D. and Bussey, T.J. 2005a. Removal of cholinergic input to perirhinal cortex disrupts object recognition but not spatial working memory in the rat. Eur. J. Neurosci. 21:2263‐2270.
   Winters, B.D. and Bussey, T.J. 2005b. Transient inactivation of perirhinal cortex disrupts encoding, retrieval, and consolidation of object recognition memory. J. Neurosci. 25:52‐61.
   Yee, B.K. 2000. Cytotoxic lesion of the medial prefrontal cortex abolishes the partial reinforcement extinction effect, attenuates prepulse inhibition of the acoustic startle reflex and induces transient hyperlocomotion, while sparing spontaneous object recognition memory in the rat. Neuroscience 95:675‐689.
   Young, J.W., Finlayson, K., Spratt, C., Marston, H.M., Crawford, N., Kelly, J.S., and Sharkey, J. 2004. Nicotine improves sustained attention in mice: evidence for involvement of the alpha7 nicotinic acetylcholine receptor. Neuropsychopharmacology 29:891‐900.
   Young, J.W., Crawford, N., Kelly, J.S., Kerr, L.E., Marston, H.M., Spratt, C., Finlayson, K., and Sharkey, J. 2006. Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice. Eur. Neuropsychopharmacol. April 29, Epub ahead of print.
   Zhang, H.T. and O'Donnell, J.M. 2000. Effects of rolipram on scopolamine‐induced impairment of working and reference memory in the radial‐arm maze tests in rats. Psychopharmacology (Berl) 150:311‐316.
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