Abstract
Prepulse inhibition (PPI) refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. PPI has been extensively employed as an assay for sensorimotor gating, and its disruption has been characterized in specific disease conditions, including schizophrenia. In animals, dopamine agonists disrupt PPI, and this disruption can be antagonized by antipsychotic drug treatment. The present study extended these fundamental findings to C57BL6 mice, and further evaluated the subjects' reaction to the prepulse stimulus alone in relation to the expression of PPI. Not only did apomorphine (2.0 mg/kg, intraperitoneal (i.p.)) attenuate PPI but it also enhanced reactivity to the prepulse stimulus. The dual effects of apomorphine appear paradoxical in view of the positive correlation, detectable in both the control and apomorphine groups, between prepulse reactivity and PPI magnitude. The present findings contradict the hypothesis that apomorphine disrupts PPI via reduced detectability or perception of the prepulse, and we further propose that enhanced distractibility may provide a parsimonious account for the dual effects of apomorphine. Moreover, haloperidol pretreatment (0.4 mg/kg, i.p.) fully antagonized the effects of apomorphine upon prepulse reactivity as well as on PPI. The present results add to our understanding of the relevance and applicability of the PPI paradigm in modeling schizophrenia-like symptoms in animals.
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Notes
We conducted additional runs of the present PPI protocol with four dead mice, and confirmed that none of these sessions generated consistent readings on prepulse-alone trials as seen in the three experiments reported here. This indicated that our measurements of prepulse reactivity did not stem from spurious vibrations associated with the delivery of the prepulse stimulus itself.
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Acknowledgements
This study was supported by the Swiss Federal Institute of Technology, Zurich. BK Yee was further supported by the National Center of Competence in Research (NCCR): Neural Plasticity and Repair, Swiss National Science Foundation. We gratefully acknowledge Dr Tobias Bast's efforts in critical thinking, and thank Alan Ipekian and Peter Schmid for their technical and editorial expertise. We also remain indebted to the anonymous reviewers for their constructive criticism in the revision of this article.
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Yee, B., Russig, H. & Feldon, J. Apomorphine-Induced Prepulse Inhibition Disruption is Associated with a Paradoxical Enhancement of Prepulse Stimulus Reactivity. Neuropsychopharmacol 29, 240–248 (2004). https://doi.org/10.1038/sj.npp.1300323
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DOI: https://doi.org/10.1038/sj.npp.1300323
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