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Altered prepulse inhibition in rats treated prenatally with the antimitotic Ara-C: an animal model for sensorimotor gating deficits in schizophrenia

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Abstract

Rationale

Sensorimotor gating disruption is one of many neurocognitive deficits seen in schizophrenia. Disorganized thought is one of the cardinal symptoms associated with sensorimotor gating. In an attempt to model sensorimotor gating deficits in rats relevant to the neurodevelopmental hypothesis for schizophrenia, we have used prenatal injections of the antimitotic drug, cytosine arabinoside (Ara-C) to subtly perturb the development of the rat CNS and disrupt sensorimotor gating.

Objective

To produce rats with either basal sensorimotor gating deficits or increased vulnerability to the disruption of sensorimotor function by apomorphine or phencyclidine (PCP). Prepulse inhibition (PPI) of the acoustic startle response was used to assess sensorimotor gating.

Methods

Three different cohorts of pregnant Sprague Dawley female rats were injected with Ara-C (30 mg/kg in saline) or saline at embryonic days 19.5 and 20.5. The Ara-C and control rats were tested for acoustic startle response and PPI at preadolescent and post-adolescent ages; postnatal day (Pnd) 35 and 56, respectively. Apomorphine (2.0 mg/kg) or phencyclidine (3.0 mg/kg), was given prior to PPI sessions in order to disrupt PPI.

Results

At Pnd 35, Ara-C treatment did not significantly affect acoustic startle amplitudes or PPI. However, at PND 56, Ara-C treated rats had significantly lower acoustic startle amplitudes and significantly diminished sensorimotor gating. Pharmacological challenge with the dopamine agonist apomorphine and the glutamate antagonist PCP significantly disrupted sensorimotor gating in the control subjects. Apomorphine did not further disrupt the existing deficit in the Ara-C treated rats. Ara-C treatment did not cause gross loss of neuronal tissue, although there was a subtle and variable disorganization of the pyramidal cell layer in the hippocampal CA2/3 region.

Conclusion

The results provide evidence to suggest that late embryonic exposure to Ara-C disrupts the circuitry involved in mediating PPI. While the dopamine agonist apomorphine caused a significant disruption in the control rats it did not further disrupt the existing deficit in the Ara-C treated rats. These data provide evidence to support the contention that modest neurodevelopmental insults can significantly affect sensorimotor gating processes in an adult onset dependent manner.

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Acknowledgements

This study was supported by a University-Industry partnership with Novartis.

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  1. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228, USA

    G. I. Elmer, J. Sydnor, H. Guard, E. Hercher & M. W. Vogel

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  1. G. I. Elmer
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  2. J. Sydnor
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  3. H. Guard
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  4. E. Hercher
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  5. M. W. Vogel
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Correspondence to M. W. Vogel.

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Elmer, G.I., Sydnor, J., Guard, H. et al. Altered prepulse inhibition in rats treated prenatally with the antimitotic Ara-C: an animal model for sensorimotor gating deficits in schizophrenia. Psychopharmacology 174, 177–189 (2004). https://doi.org/10.1007/s00213-003-1757-7

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  • DOI: https://doi.org/10.1007/s00213-003-1757-7

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