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Metabotropic Glutamate Receptor Subtype 7 Is Essential for Ejaculation

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Abstract

Metabotropic glutamate receptor subtype 7 (mGluR7) is a member of the group III mGluRs, which are negatively coupled to adenylate cyclase via Gi/Go proteins and localized to presynaptic active zones of the mammalian central nervous system (CNS). To elucidate the mechanism of impaired reproductivity of mGluR7 knockout (KO) mice, we investigated sexual behavior in this line, which exhibits ejaculatory disorder, although with normal sexual motivation and erectile function. To identify the site of action within the CNS responsible for the effect of mGluR7 on ejaculation, we then used a para-chloroamphetamine (PCA)-induced ejaculation model. Intrathecal administration of the mGluR7-selective antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) into the lumbosacral spinal cord inhibited PCA-induced ejaculation. Immunohistochemistry revealed mGluR7-like immunoreactivity (LI) expressed in the same area where lumbar spinothalamic (LSt) cells regulate the parasympathetic ejaculatory pathway. At high magnification, the apposition of mGluR7-LI puncta and neuronal nitric oxide synthase (nNOS)-LI-positive putative parasympathetic preganglionic neurons was evident. These results indicate that mGluR7 in the lumbosacral spinal cord regulates ejaculation by potentiating the excitability of parasympathetic preganglionic neurons. The ejaculatory disorder is a major issue in the field of male reproductive function. Erectile dysfunction (ED) can be treated by phosphodiesterase type 5 inhibitors like sildenafil (Viagra®), but the ejaculatory disorder cannot. Lack of understanding of the ejaculatory mechanism hinders the development of therapies for ejaculatory problems. This study is the first to demonstrate that mGluR7 regulates ejaculation and the results provide insight into the mechanism of ejaculation as well as a strategy for future therapies to treat ejaculatory disorders in humans.

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Acknowledgments

We especially thank Dr. Herman van der Putten from the Novartis Institutes for BioMedical Research (Basel, Switzerland) for providing the mGluR7 KO mice and Dr. Ryoichiro Kageyama for providing an excellent research environment.

Funding

This work was supported by the Japan Society for the Promotion of Science KAKENHI (Grant Numbers 20500313 and 23500415 to MMT).

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Authors and Affiliations

  1. Department of Urology, Shiga University of Medical Science, Otsu, Japan

    Miwako Masugi-Tokita, Keiji Tomita, Kenichi Kobayashi, Tetsuya Yoshida, Susumu Kageyama & Akihiro Kawauchi

  2. World Premier International Research Center Initiative–Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan

    Miwako Masugi-Tokita

  3. Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan

    Miwako Masugi-Tokita

  4. Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Setouchi, Japan

    Hirotaka Sakamoto

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  1. Miwako Masugi-Tokita
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Correspondence to Miwako Masugi-Tokita.

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All animal protocols were compliant with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Committee for Animal Research, Shiga University of Medical Science, and Kyoto University. Every effort was made to minimize any suffering of the animals used in this study. Animals were euthanized with cervical dislocation or CO2 inhalation in a chamber following approved protocols.

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Masugi-Tokita, M., Tomita, K., Kobayashi, K. et al. Metabotropic Glutamate Receptor Subtype 7 Is Essential for Ejaculation. Mol Neurobiol 57, 5208–5218 (2020). https://doi.org/10.1007/s12035-020-02090-2

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