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Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice

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Abstract

Rationale

The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer’s disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice.

Objectives

We examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice.

Methods

Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured.

Results

Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2–3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors.

Conclusions

Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.

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Acknowledgments

This study was supported in part by KAKENHI (25460099 (YA), 26293020 (HH), 26670122 (HH), 15H01288 (HH), and 15K18874 (YO)); the Neuropsychiatry Drug Discovery Consortium established by Dainippon Sumitomo Pharma Co., Ltd. (Japan) with Osaka University (TM and HH); Takeda Science Foundation (Japan) (YA); Research Foundation for Pharmaceutical Sciences (Japan) (YA); the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (HH); and a fund by Novartis Pharma K.K. (Japan) (110601 (TM)).

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    Authors and Affiliations

    1. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Kosuke Higashino, Yukio Ago, Takahiro Umeki, Yusuke Onaka & Hitoshi Hashimoto

    2. Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Shigeru Hasebe & Kazuhiro Takuma

    3. United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Hitoshi Hashimoto & Kazuhiro Takuma

    4. Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Toshio Matsuda

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    1. Kosuke Higashino
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    2. Yukio Ago
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    Corresponding author

    Correspondence to Toshio Matsuda.

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    Kosuke Higashino and Yukio Ago contributed equally to this work.

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    Higashino, K., Ago, Y., Umeki, T. et al. Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice. Psychopharmacology 233, 521–528 (2016). https://doi.org/10.1007/s00213-015-4123-7

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    • DOI: https://doi.org/10.1007/s00213-015-4123-7

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