Models of Schizophrenia: Phencyclidine Disruption of Prepulse Inhibition (PPI) of Startle in Rats

John H. Kehne1, Diane C. Hoffman1, James V. Cassella1

1 Neurogen Corporation, Branford, Connecticut
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.15
DOI:  10.1002/0471141755.ph0515s03
Online Posting Date:  May, 2001
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Abstract

Modern theories of schizophrenia implicate deficits in glutamatergic transmission in the etiology of this disorder. This unit describes an animal model in which a deficit in glutamatergic transmission is induced pharmacologically by the NMDA receptor ion channel blocker phencyclidine. Reversal of the resulting behavioral impairment, the reduction of sensory‚Äźmotor gating as measured by prepulse inhibition, can be used as a method for evaluating novel treatments for schizophrenia.

     
 
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Table of Contents

  • Strategic Planning: Experimental Materials
  • Basic Protocol 1: Prepulse Inhibition (PPI) of Startle in Rats
  • Reagents and Solutions
  • Commentary
  • Figures
     
 
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Materials

Basic Protocol 1: Prepulse Inhibition (PPI) of Startle in Rats

  Materials
  • Adult male Sprague‐Dawley rats (200 to 250 g), 10 to 15 per dose group
  • Test compound solution(s) (e.g., PCP, MK 801, apomorphine, haloperidol; see recipe)
  • Apparatus for measuring acoustic startle response in rats (Fig. ; San Diego Instruments or MED Associates)
  • Sound‐level meter (Bruel & Kjaer)
  • Cage calibrator (San Diego Instruments or MED Associates)
  • Data processing system (see Strategic Planning, point 6)
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Figures

Videos

Literature Cited

Literature Cited
   Braff, D.L., Swerdlow, N.R., and Geyer, M.A. 1995. Gating and habituation deficits in the schizophrenia disorders. Clin. Neurosci. 3:131‐139.
   Carlsson, M. and Carlsson, A. 1990. Interactions between glutamatergic and monoaminergic systems within the basal ganglia: Implications for schizophrenia and Parkinson's disease. Trends Neurosci. 13:272‐276.
   Cassella, J.V. and Davis, M. 1986. The design and calibration of a startle measurement system. Physiol. Behav. 36:377‐383.
   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.
   Hoffman, H.S. and Ison, J.R. 1980. Reflex modification in the domain of startle. I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol. Rev. 87:175‐189.
   Hoffman, D.C., Donovan, H., and Cassella, J.V. 1993. The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK‐801. Psychopharmacology 111:339‐344.
   Horlington, M. 1970. Startle response circadian rhythm in rats: Lack of correlation with motor activity. Physiol. Behav. 5:49‐53.
   Kehne, J.H., Cassella, J.V., and Davis, M. 1988. Anxiolytic effects of buspirone and gepirone in the fear‐potentiated startle paradigm. Psychopharmacology 94:8‐13.
   Kehne, J.H., McCloskey, T.C., Taylor, V.L., Black, C.K., Abbate, G.M., and Schmidt, C.J. 1992. Effects of the serotonin releasers 3,4‐methylenedioxymethamphetamine (MDMA), 4‐chloroamphetamine (PCA), and fenfluramine on acoustic and tactile startle reflexes in rats. J. Pharmacol. Exp. Ther. 260:78‐89.
   Kehne, J.H., Padich, R.A., McCloskey, T.C., Taylor, V.L., and Schmidt, C.J. 1996. 5‐HT modulation of auditory and visual sensorimotor gating. I. Effects of 5‐HT releasers on sound and light prepulse inhibition in Wistar rats. Psychopharmacology 124:95‐106.
   Krystal, J.H., Karper, L.P., Seibyl, J.P., Freeman, G.K., Delaney, R., Bremmer, J.D., Heninger, G.R., Bowers, M.B., and Charney, D.S. 1994. Subanesthetic doses of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive and neuroendocrine responses. Arch. Gen. Psychiatry 51:199‐214.
   Mansbach, R.S. and Geyer, M.A. 1989. Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2:299‐308.
   Mansbach, R.S., Geyer, M.A., and Braff, D.L. 1988. Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology 94:507‐514.
   Padich, R.A., McCloskey, T.C., and Kehne, J.H. 1996. 5‐HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5‐HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5‐HT agonists in Wistar rats. Psychopharmacology 124:107‐116.
   Rigdon, G.C. 1990. Differential effects of apomorphine on prepulse inhibition of acoustic startle reflex in two rat strains. Psychopharmacology 102:419‐421.
   Sams‐Dodd, F. 1996. Phencyclidine‐induced stereotyped behavior and social isolation in rats: A possible animal model of schizophrenia. Behav. Pharmacol. 7:3‐23.
Key References
   Braff, D.L., Grillon, C., and Geyer, M.A. 1992. Gating and habituation of the startle reflex in schizophrenic patients. Arch. Gen. Psychiatry. 49:206‐215.
  Reviews clinical evidence that schizophrenic patients have sensorimotor gating deficits as measured using prepulse inhibition techniques.
   Geyer, et. al., 1990. See above.
  Reviews the phenomenology of PPI.
   Hoffman, and Ison, 1980. See above.
  Reviews clinical and preclinical evidence for sensorimotor gating deficits as measured using prepulse inhibition techniques.
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