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Effects of selective calcium-permeable AMPA receptor blockade by IEM 1460 on psychotomimetic-induced hyperactivity in the mouse

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
  • Published:
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Abstract

Diminished glutamate neurotransmission via the N-methyl-d-aspartate type glutamate receptor (NMDAR) has been considered to be involved in the pathophysiology of schizophrenia based upon the observation that the antagonists and autoantibodies of NMDAR cause positive, negative and cognitive symptomatologies similar to those of schizophrenia. The possible reduced extracellular levels of d-serine by overstimulation of the calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor (CP-AMPAR) following the NMDAR hypofunction-induced compensatory increase in the glutamate release could aggravate the NMDAR hypofunction in the brain of the drug- or antibody-associated psychoses and schizophrenia, because d-serine is an intrinsic coagonist for the NMDAR. To obtain an insight into the therapeutic approach to such a glutamate-linked psychotic state, we have studied the effects of the systemic administration of the CP-AMPAR-selective antagonist, IEM 1460 (N,N,N-trimethyl-5- [(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]-1-pentanaminium bromide hydrobromide), on the hyperactivity following an injection of a schizophrenomimetic NMDAR antagonist, phencyclidine, in the mouse. The subcutaneous IEM 1460 application produced a dose-dependent inhibition of the increased movement counts after the subcutaneous injection of phencyclidine. This inhibiting influence was also seen on the hyperactivity elicited by another NMDAR antagonist, dizocilpine. Moreover, the IEM 1460 administration attenuated the ability of a schizophrenomimetic dopamine agonist, methamphetamine, to increase spontaneous movements. These findings indicate that dysregulation of the CP-AMPAR could, at least in part, be implicated in the glutamate pathology of schizophrenia and/or related psychotic symptoms and be a potential target for the development of their novel treatment.

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Acknowledgements

This work was supported by the Tokyo Medical and Dental University funds.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Masakazu Umino, Asami Umino & Toru Nishikawa

  2. Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Masakazu Umino, Asami Umino & Toru Nishikawa

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  1. Masakazu Umino
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  2. Asami Umino
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  3. Toru Nishikawa
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Correspondence to Toru Nishikawa.

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Umino, M., Umino, A. & Nishikawa, T. Effects of selective calcium-permeable AMPA receptor blockade by IEM 1460 on psychotomimetic-induced hyperactivity in the mouse. J Neural Transm 125, 705–711 (2018). https://doi.org/10.1007/s00702-017-1827-3

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  • DOI: https://doi.org/10.1007/s00702-017-1827-3

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