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Effects of acute and chronic clozapine on d-amphetamine-induced disruption of auditory gating in the rat

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Abstract

Rationale

Auditory gating deficits observed in patients with schizophrenia have been modeled in animals administered the indirect-acting monoaminergic agonist, d-amphetamine (AMPH). The atypical antipsychotic drug clozapine (CLOZ) reverses the disruption of auditory gating in schizophrenic patients. However, its effects on psychostimulant-induced deficits in animals have yet to be assessed.

Objectives

In the present series of experiments, an auditory evoked potential paradigm was used to: (a) confirm the ability of AMPH to alter auditory gating in the anesthetized rat, (b) specify the nature of the accompanying change(s) in evoked potential waveforms and (c) determine the effects of CLOZ administration on AMPH-induced alterations in auditory gating.

Methods

We compared the effects of acute (5 mg/kg, i.p.) and chronic (28 days, 0.5 mg/ml in drinking water) CLOZ on AMPH-induced (1.8 mg/kg, i.p.) alterations in evoked potentials recorded in the hippocampus of anesthetized rats during presentation of a pair of identical tones. Gating was assessed by comparing the amplitude of conditioning and test responses in CLOZ and AMPH-treated rats.

Results

The ratio of test to conditioning response amplitude (T/C ratio) was not altered by vehicle or CLOZ alone. However, T/C ratio was significantly increased following AMPH due to suppression of the conditioning response. Acute but not chronic CLOZ attenuated but did not prevent the increase in T/C ratio.

Conclusions

Qualitative differences between the idiopathic gating deficits observed in schizophrenic patients and AMPH-induced increases in T/C ratio in animals limit this models utility as a means of evaluating the ability of atypical antipsychotic drugs to restore normal sensory gating.

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Acknowledgements

The authors wish to express their gratitude to Drs. R. Buchanan and G. Elmer, Ms. Ann Summerfelt and Lucy Clerkin for their insightful comments and editorial assistance during the preparation of this manuscript. Supported by a grant from Novartis Pharma AG.

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  1. Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA

    Brian Joy, Robert P. McMahon & Paul D. Shepard

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  1. Brian Joy
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  2. Robert P. McMahon
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  3. Paul D. Shepard
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Correspondence to Paul D. Shepard.

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Joy, B., McMahon, R.P. & Shepard, P.D. Effects of acute and chronic clozapine on d-amphetamine-induced disruption of auditory gating in the rat. Psychopharmacology 174, 274–282 (2004). https://doi.org/10.1007/s00213-003-1731-4

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  • DOI: https://doi.org/10.1007/s00213-003-1731-4

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