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The Journal of Neuroscience, January 15, 2001, 21(2):750-757
Hyperfunction of Dopaminergic and Serotonergic Neuronal Systems
in Mice Lacking the NMDA Receptor  1 Subunit
Yoshiaki
Miyamoto1,
Kiyofumi
Yamada1,
Yukihiro
Noda1,
Hisashi
Mori2,
Masayoshi
Mishina2, and
Toshitaka
Nabeshima1
1 Department of Neuropsychopharmacology and Hospital
Pharmacy, Nagoya University Graduate School of Medicine, Nagoya
466-8560, Japan, and 2 Department of Molecular Neurobiology
and Pharmacology, School of Medicine, University of Tokyo, Tokyo
113-0033, Japan
NMDA receptors, an ionotropic subtype of glutamate receptors
(GluRs) forming high Ca2+-permeable cation channels,
are composed by assembly of the GluR subunit (NR1) with any one of
four GluR subunits (GluR1-4; NR2A-D). In the present study, we
investigated neuronal functions in mice lacking the GluR1 subunit.
GluR1 mutant mice exhibited a malfunction of NMDA receptors, as
evidenced by alterations of [3H]MK-801 binding as
well as 45Ca2+ uptake through the NMDA
receptors. A postmortem brain analysis revealed that both dopamine and
serotonin metabolism were increased in the frontal cortex and striatum
of GluR1 mutant mice. The NMDA-stimulated
[3H]dopamine release from the striatum was
increased, whereas [3H]GABA release was markedly
diminished in GluR1 mutant mice. When (+)bicuculline, a
GABAA receptor antagonist, was added to the superfusion
buffer, NMDA-stimulated [3H]dopamine release was
significantly increased in wild-type, but not in the mutant mice.
GluR1 mutant mice exhibited an increased spontaneous locomotor
activity in a novel environment and an impairment of latent learning in
a water-finding task. Hyperlocomotion in GluR1 mutant mice was
attenuated by treatment with haloperidol and risperidone, both of which
are clinically used antipsychotic drugs, at doses that had no effect in
wild-type mice. These findings provide evidence that NMDA receptors are
involved in the regulation of behavior through the modulation of
dopaminergic and serotonergic neuronal systems. In addition, our
findings suggest that GluR1 mutant mice are useful as an animal
model of psychosis that is associated with NMDA receptor malfunction
and hyperfunction of dopaminergic and serotonergic neuronal systems.
Key words:
NMDA receptor; GluR1 subunit; dopaminergic neuronal
system; serotonergic neuronal system; hyperlocomotion; schizophrenia
Copyright © 2001 Society for Neuroscience 0270-6474/01/212750-08$05.00/0
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