Role of the NMDA receptor GluN2D subunit in the expression of ketamine-induced behavioral sensitization and region-specific activation of neuronal nitric oxide synthase

• DOI: 10.1016/j.neulet.2015.10.049
• Publication Date: 2015-10-30T15:04:10Z
• Authors: Toshifumi Yamamoto; Tomomi Nakayama; Junji Yamaguchi; Maaya Matsuzawa; Masayoshi Mishina; Kazutaka Ikeda; Hideko Yamamoto
• Keywords: Male; Mice, Knockout; Neurons; 0301 basic medicine; Psychotropic Drugs; Prefrontal Cortex; Nitric Oxide Synthase Type I; Motor Activity; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Corpus Striatum; Enzyme Activation; Mice, Inbred C57BL; Protein Subunits; 03 medical and health sciences; Organ Specificity; Animals; Ketamine; NADP

The present study aimed to investigate the involvement of the NMDA receptor (NMDAR) and/or nitric oxide (NO) pathway in ketamine-induced behavioral sensitization. Mice received repeated subcutaneous administration of ketamine (25mg/kg), once daily or once weekly for a total of five doses. Even three administrations of ketamine, daily or weekly, induced a rapid increase in locomotor activity in wild-type (WT), but not in GluN2D knockout (GluN2D-KO) mice. Furthermore, for WT mice receiving daily ketamine, elevated locomotor activity was maintained after a 1-month withdrawal period; however, this was not the case when ketamine was administered weekly. The effect of acute ketamine on nNOS activities was estimated with nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry. Ketamine rapidly increased the number of NADPH-d activated cells and strongly stained dendrites in the dorsal striatum and prefrontal cortex of WT mice, but not GluN2D-KO mice. These results suggest that ketamine-induced locomotor sensitization and nNOS activation in the frontal cortex-striatum neuronal circuit are positively correlated and that the NMDAR GluN2D subunit plays an important role in the acquisition and maintenance of ketamine-induced behavioral sensitization.