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Essential role of NMDA receptor channel ε4 subunit (GluN2D) in the effects of phencyclidine, but not methamphetamine.

Hagino Y, Kasai S, Han W, Yamamoto H, Nabeshima T, Mishina M, Ikeda K - PLoS ONE (2010)

Bottom Line: 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 results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.

View Article: PubMed Central - PubMed

Affiliation: Division of Psychobiology, Tokyo Institute of Psychiatry, Tokyo, Japan.

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. 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 ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.

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Locomotor activity in wildtype, GluRε1−/−, and GluRε4−/− mice in a novel environment.Locomotor activity was measured for 180 min. Each point represents the mean ± SEM (n = 34–50). *p<0.05, **p<0.01, ***p<0.001, compared with wildtype mice (one-way ANOVA followed by Fisher's PLSD post hoc test).
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pone-0013722-g003: Locomotor activity in wildtype, GluRε1−/−, and GluRε4−/− mice in a novel environment.Locomotor activity was measured for 180 min. Each point represents the mean ± SEM (n = 34–50). *p<0.05, **p<0.01, ***p<0.001, compared with wildtype mice (one-way ANOVA followed by Fisher's PLSD post hoc test).

Mentions: Locomotor activity in a novel environment was different between wildtype, GluRε1−/−, and GluRε4−/− mice during the habituation period (mixed-design ANOVA: genotype, F2,123 = 35.423, p<0.0001; time, F2,123 = 486.554, p<0.0001; genotype × time, F4,123 = 15.337, p<0.0001) (Fig. 3). Locomotor activity in a novel environment during the 60 min period increased in GluRε1−/− mice (p = 0.0002, unpaired t-test) but decreased in GluRε4−/− mice (p<0.0001, Student's t-test) compared with wildtype mice. GluRε1−/− mice did not habituate during the 180 min period compared with wildtype mice (p<0.0001, Student's t-test).


Essential role of NMDA receptor channel ε4 subunit (GluN2D) in the effects of phencyclidine, but not methamphetamine.

Hagino Y, Kasai S, Han W, Yamamoto H, Nabeshima T, Mishina M, Ikeda K - PLoS ONE (2010)

Locomotor activity in wildtype, GluRε1−/−, and GluRε4−/− mice in a novel environment.Locomotor activity was measured for 180 min. Each point represents the mean ± SEM (n = 34–50). *p<0.05, **p<0.01, ***p<0.001, compared with wildtype mice (one-way ANOVA followed by Fisher's PLSD post hoc test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2965660&req=5

pone-0013722-g003: Locomotor activity in wildtype, GluRε1−/−, and GluRε4−/− mice in a novel environment.Locomotor activity was measured for 180 min. Each point represents the mean ± SEM (n = 34–50). *p<0.05, **p<0.01, ***p<0.001, compared with wildtype mice (one-way ANOVA followed by Fisher's PLSD post hoc test).
Mentions: Locomotor activity in a novel environment was different between wildtype, GluRε1−/−, and GluRε4−/− mice during the habituation period (mixed-design ANOVA: genotype, F2,123 = 35.423, p<0.0001; time, F2,123 = 486.554, p<0.0001; genotype × time, F4,123 = 15.337, p<0.0001) (Fig. 3). Locomotor activity in a novel environment during the 60 min period increased in GluRε1−/− mice (p = 0.0002, unpaired t-test) but decreased in GluRε4−/− mice (p<0.0001, Student's t-test) compared with wildtype mice. GluRε1−/− mice did not habituate during the 180 min period compared with wildtype mice (p<0.0001, Student's t-test).

Bottom Line: 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 results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.

View Article: PubMed Central - PubMed

Affiliation: Division of Psychobiology, Tokyo Institute of Psychiatry, Tokyo, Japan.

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. 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 ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.

Show MeSH
Related in: MedlinePlus