REPEATED KETAMINE ADMINISTRATION PRODUCES UP-REGULATION OF MUSCARINICACETYLCHOLINE-RECEPTORS IN THE FOREBRAIN, AND REDUCES BEHAVIORAL SENSITIVITY TO SCOPOLAMINE IN MICE

To study the effects of repeated ketamine administration on central mu scarinic acetylcholine receptors (mAchRs), ddY male mice were administ ered 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 th e forebrain (FB), cerebellum (CB) and brainstem (BS), using [H-3]quinu clidinyl benzilate ([H-3]QNB) as a ligand. In addition, we examined wh ether repeated ketamine (12.5, 25 and 50 mg/kg) or saline (five times) could modify the hyperlocomotion induced by scopolamine (0.5 mg/kg, S C) (a muscarinic antagonist), using a behavior-pharmacological techniq ue. Repeating the ketamine administration resulted in a significant in crease in the receptor density value (B-max) for [H-3]QNB only in FB, dependent on the numbers of administrations (1270 +/- 33 fmol/mg prote in for a single dose, 1620 +/- 59 for four treatments, 1738 +/- 70 for five treatments without any change in apparent affinity (defined as t he reciprocal of the dissociation constant) (Kd). A competitive inhibi tion study of repeated (5 times) administration of ketamine failed to detect any subtype-specific changes in mAchRs. Repeated ketamine admin istration reduced the scopolamine-induced hyperlocomotion in a dose-re lated way, and the changes were significant at 50 mg/kg. Our results s uggest that repeated ketamine administration produces an up-regulation of mAchRs, and this change may be associated with altered Ach transmi ssion in the central nervous system.