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Effects of the H3 antagonist, thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats

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Abstract

Rationale

Recent studies have raised the possibility that antagonists of H3 histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia.

Objectives

The purpose of this study was to determine if a prototypical H3 antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia.

Methods

The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg).

Results

Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment.

Conclusions

H3 receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.

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Acknowledgments

This research was supported by the National Center for Research Resources Grant P20 RR16481 and National Institute of Mental Health Grant R15 MH076788. We would like to acknowledge the NIMH Chemical Synthesis and Drug Supply Program providing the thioperamide used in this study. The experiments reported here comply with Current Guide for the Care and Use of Laboratory Animals (USPHS) and were performed under a protocol approved by the Northern Kentucky University Institutional Animal Use and Care Committee.

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Authors and Affiliations

  1. Department of Psychology, Northern Kentucky University, 1 Nunn Drive, Highland Heights, KY, 41076, USA

    Mark E. Bardgett, Megan Points, John Roflow, Meredith Blankenship & Molly S. Griffith

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  1. Mark E. Bardgett
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  2. Megan Points
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  4. Meredith Blankenship
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  5. Molly S. Griffith
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Correspondence to Mark E. Bardgett.

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Bardgett, M.E., Points, M., Roflow, J. et al. Effects of the H3 antagonist, thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats. Psychopharmacology 205, 589–597 (2009). https://doi.org/10.1007/s00213-009-1566-8

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  • DOI: https://doi.org/10.1007/s00213-009-1566-8

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