title: Repeated ketamine administration produces up-regulation of muscarinic acetylcholine receptors in the forebrain, and reduces behavioral sensitivity to scopolamine in mice.
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 dose-related 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.
authors.affiliation: Department of Anesthesiology and Reanimatology, Gunma University School of Medicine and Hospital, Maebashi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Morita
authors.forename: S
authors.initials: S
authors.lastname: Hitomi
authors.forename: S
authors.initials: S
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Fujita
authors.forename: Y
authors.initials: Y
authors.lastname: Uchihashi
authors.forename: H
authors.initials: H
authors.lastname: Kuribara
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D007649:Ketamine / Q000494:pharmacology*; D007700:Kinetics; D008124:Locomotion; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists; D016548:Prosencephalon / Q000187:drug effects*; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate; D007649:Ketamine; D012601:Scopolamine