SY07-1 * INVOLVEMENT OF NMDA RECEPTOR GLUN2D SUBUNIT IN PHENCYCLIDINE EFFECTS

Abstract

Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. We investigated the effect of PCP on extracellular levels of DA (DAex) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis and locomotor activity in mice lacking the NMDA receptor channel GluN2A or GluN2D subunit. PCP significantly increased DAex in wildtype and GluN2A knockout mice, but not in GluN2D knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluN2D knockout mice (PLoS ONE, 2010). Furthermore, DNA array experiments revealed that PCP-induced fos expression was abolished in GluN2D knockout mice (Mol Brain, 2013). These results suggest that PCP enhances dopaminergic transmission, increases locomotor activity, and induces fos expression by acting at GluN2D. GluN2D may be a new target for pharmacotherapy of PCP dependence and schizophrenia.