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Prepulse inhibition of the startle reflex and response to antipsychotic treatments in two outbred mouse strains in comparison to the inbred DBA/2 mouse

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Abstract

Rationale

Naturally low prepulse inhibition (PPI) in DBA/2 mice is increased by marketed antipsychotics and compounds acting at novel targets relevant to schizophrenia. Whether other mouse strains with naturally low PPI respond similarly and could be translational models of schizophrenia is unknown.

Objective

Baseline levels of PPI were determined in outbred CF-1 and Black Swiss mice. CF-1 and Black Swiss mice were then compared to DBA/2 mice for their responses to typical (haloperidol) and atypical (clozapine) antipsychotics and to compounds with potential antipsychotic activity, a histamine H3 receptor antagonist (thioperamide) and a glycine transporter-1 inhibitor (SSR504734).

Results

CF-1 and Black Swiss mice had naturally low PPI, similar to the level in C57BL/6 mice, but higher than that in DBA/2 mice. Haloperidol (0.3–1 mg/kg) increased PPI in DBA/2, CF-1, and Black Swiss mice. Clozapine (3 mg/kg) increased PPI in DBA/2 and CF-1 mice, but not in Black Swiss mice. Thioperamide (10–30 mg/kg) and SSR504734 (30 mg/kg) increased PPI only in DBA/2 mice. Strain differences in PPI responsiveness were not due to differences in brain concentrations of the tested compounds.

Conclusions

CF-1 mice with naturally low PPI may be useful for testing typical and atypical antipsychotics while Black Swiss mice only responded to a typical antipsychotic. DBA/2 mice remain the only strain with naturally low PPI that responds to marketed antipsychotics, as well as to compounds with novel mechanisms of action. Thus, DBA/2 mice may be the strain of choice for screening novel chemical entities for their ability to increase PPI.

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Acknowledgments

The authors thank Lisa Aimone, Kelli Zeigler, and Rebecca Brown for performing the bioanalytical studies. Cephalon, Inc. employed the authors and sponsored this research. The experiments described in this manuscript comply with the current laws of the United States, the country in which they were performed.

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Author notes

  1. Dorothy G. Flood

    Present address: EnVivo Pharmaceuticals, Inc, 480 Aresenal St, Watertown, MA, 02472, USA

  2. Michael J. Marino

    Present address: Merck and Co, 770 Sumneytown Pike, West Point, PA, 19486, USA

Authors and Affiliations

  1. Worldwide Discovery Research, Cephalon, Inc, 145 Brandywine Parkway, West Chester, PA, 19380, USA

    Dorothy G. Flood, Eva Zuvich, Michael J. Marino & Maciej Gasior

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  1. Dorothy G. Flood
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  2. Eva Zuvich
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Correspondence to Dorothy G. Flood.

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Flood, D.G., Zuvich, E., Marino, M.J. et al. Prepulse inhibition of the startle reflex and response to antipsychotic treatments in two outbred mouse strains in comparison to the inbred DBA/2 mouse. Psychopharmacology 215, 441–454 (2011). https://doi.org/10.1007/s00213-011-2196-5

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  • DOI: https://doi.org/10.1007/s00213-011-2196-5

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