The NMDA subtype of glutamate receptor (GluR) plays an important role in excitatory neurotransmission, synaptic plasticity, brain development, and neurodegeneration. NMDA receptors are inherent high Ca(2+)-permeable channels, which are formed by heteromeric assembly of the GluR zeta 1 subunit (NR1) and any one of four GluR epsilon subunits (GluR epsilon 1-4; NR2A-D). Mice lacking the GluR epsilon 1 subunit exhibited a malfunction of NMDA receptors, as evidenced by reduction of NMDA receptor channel current, hippocampal long-term potentiation, [3H]MK-801 binding, and NMDA-stimulated 45Ca2+ uptake. A biochemical analysis revealed a hyperfunction of dopaminergic and serotonergic neuronal systems in the frontal cortex and striatum of GluR epsilon 1 mutant mice. The enhancement of dopaminergic neuronal activity in the striatum, at least, due to the disinhibition of inhibitory GABAergic neuronal input. GluR epsilon 1 mutant mice showed an increase of locomotor activity in a novel environment attributed to the hyperfunction of the dopaminergic neuronal system, and an impairment of spatial, contextual, and latent learning. These findings provide evidence that NMDA receptors regulate behavior through the modulation of not only glutamatergic but also GABAergic and dopaminergic neuronal systems. Moreover, it is suggested that GluR epsilon 1 mutant mice are useful as an animal model, which is associated with the malfunction of NMDA receptors and hyperfunction of the dopaminergic neuronal system.