Essential Role of NMDA Receptor Channel ε4 Subunit (GluN2D) in the Effects of Phencyclidine, but Not Methamphetamine

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. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex)) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel epsilon 1 or epsilon 4 subunit (GluR epsilon 1 [GluN2A] or GluR epsilon 4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluR epsilon 1 knockout mice, but not in GluR epsilon 4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluR epsilon 4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluR epsilon 4.