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MitoPark mice, an animal model of Parkinson’s disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A2A antagonist SCH 412348

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Abstract

Rationale

Psychoses are debilitating side effects associated with current dopaminergic treatments for Parkinson's disease (PD). Prepulse inhibition (PPI), in which a non-startling stimulus reduces startle response to a subsequent startle-eliciting stimulus, is important in filtering out extraneous sensory stimuli. PPI deficits induced by dopamine agonists can model symptoms of psychosis. Adenosine A2A receptor antagonists, being developed as novel PD treatments, indirectly modulate dopamine signaling in the basal ganglia and may have an improved psychosis profile which could be detected using the PPI model.

Objectives

The aims of this study is to characterize PPI in MitoPark mice, which exhibit progressive loss of dopamine signaling and develop a Parkinson-like motor phenotype, and assess standard and novel PD treatment effects on PPI in MitoPark mice, which more closely mimic the basal ganglia dopamine status of PD patients.

Results

MitoPark mice displayed enhanced PPI as dopamine tone decreased with age, consistent with studies in intact mice that show enhanced PPI in response to dopamine antagonists. Paradoxically, older MitoParks were more sensitive to PPI disruption when challenged with dopamine agonists such as apomorphine or pramipexole. Alternatively, SCH 412348, an adenosine A2A antagonist, did not disrupt PPI in MitoPark mice at doses that normalized hypoactivity.

Conclusion

Use of MitoPark mice in the PPI assay to assess the potential for PD treatment to produce psychoses likely represents a more disease-relevant model. SCH 412348 does not differentially disrupt PPI as do dopamine agonists, perhaps indicative of an improved psychosis profile of adenosine A2A antagonists, even in PD patients with decreased dopamine tone in the basal ganglia.

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Acknowledgment

The authors would like to thank Charles Joseph for the pharmacokinetic analysis of plasma and brain exposures of pramipexole and SCH 412348 in MitoPark mice and age-matched controls.

Disclosure

SMG, RH, and LAH are responsible for the work described in this paper. All authors were involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis, and interpretation of data; and drafting the manuscript and/or revising the manuscript for important intellectual content. All authors provided final approval of the version to be published.

Conflict of interest

SMG, RH, and LAH are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., who may own stock and/or hold stock options in the Company.

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Authors and Affiliations

  1. Neuroscience Franchise, Merck Research Laboratories, 2015 Galloping Hill Road, K-15-C209, Kenilworth, NJ, 07033, USA

    Steven M. Grauer & Lynn A. Hyde

  2. Department of In Vivo Pharmacology (Neuroscience), Merck Research Laboratories, 2015 Galloping Hill Road, K-15-C209, Kenilworth, NJ, 07033, USA

    Robert Hodgson

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  1. Steven M. Grauer
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Correspondence to Steven M. Grauer.

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Grauer, S.M., Hodgson, R. & Hyde, L.A. MitoPark mice, an animal model of Parkinson’s disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A2A antagonist SCH 412348. Psychopharmacology 231, 1325–1337 (2014). https://doi.org/10.1007/s00213-013-3320-5

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