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Repeated ketamine administration produces up-regulation of muscarinic acetylcholine receptors in the forebrain, and reduces behavioral sensitivity to scopolamine in mice

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Abstract

To study the effects of repeated ketamine administration on central muscarinic acetylcholine receptors (mAchRs), ddY male mice were administered subcutaneous doses of 25 mg/kg ketamine every 3 days for a total of five times. Receptor binding assays of mAchR were carried out in the forebrain (FB), cerebellum (CB) and brainstem (BS), using [3H]quinuclidinyl benzilate ([3H]QNB) as a ligand. In addition, we examined whether repeated ketamine (12.5, 25 and 50 mg/kg) or saline (five times) could modify the hyperlocomotion induced by scopolamine (0.5 mg/kg, SC) (a muscarinic antagonist), using a behavior-pharmacological technique. Repeating the ketamine administration resulted in a significant increase in the receptor density value (Bmax) for [3H]QNB only in FB, dependent on the numbers of administrations (1270 ± 33 fmol/mg protein for a single dose, 1620 ± 59 for four treatments, 1738 ± 70 for five treatments without any change in apparent affinity (defined as the reciprocal of the dissociation constant) (Kd). A competitive inhibition study of repeated (5 times) administration of ketamine failed to detect any subtype-specific changes in mAchRs. Repeated ketamine administration reduced the scopolamine-induced hyperlocomotion in a doserelated way, and the changes were significant at 50 mg/kg. Our results suggest that repeated ketamine administration produces an up-regulation of mAchRs, and this change may be associated with altered Ach transmission in the central nervous system.

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Authors and Affiliations

  1. Department of Anesthesiology and Reanimatology, Gunma University School of Medicine and Hospital, 3-39-22 Showa-machi, 371, Maebashi, Japan

    T. Morita, S. Hitomi, S. Saito & T. Fujita

  2. Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, 359, Tokorozawa, Japan

    Y. Uchihashi

  3. Department of Neurobiology, Behavior Research Institute, Gunma University School of Medicine, 3-39-22 Showa-machi, 371, Maebashi, Japan

    H. Kuribara

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  1. T. Morita
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  2. S. Hitomi
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  4. T. Fujita
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  5. Y. Uchihashi
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Morita, T., Hitomi, S., Saito, S. et al. Repeated ketamine administration produces up-regulation of muscarinic acetylcholine receptors in the forebrain, and reduces behavioral sensitivity to scopolamine in mice. Psychopharmacology 117, 396–402 (1995). https://doi.org/10.1007/BF02246210

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  • DOI: https://doi.org/10.1007/BF02246210

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