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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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Effects of acute PCP on DAex in the striatum and PFC in wildtype, GluRε1−/−, and GluRε4−/− mice.(A, C) Temporal pattern of DAex before and after s.c. saline (Sal) or PCP (3 mg/kg) injection. The arrows indicate the drug injection time. Each point represents the mean ± SEM of the percentage of DAex baseline. (B, D) Histogram representing the mean AUC ± SEM of DAex during the 180 min period after saline or PCP injection (n = 5–11). ***p<0.001, compared with saline group of the same genotype; #p<0.05, ##p<0.01, comparisons between genotypes in the same drug treatment (two-way ANOVA followed by Fisher's PLSD post hoc test).
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pone-0013722-g002: Effects of acute PCP on DAex in the striatum and PFC in wildtype, GluRε1−/−, and GluRε4−/− mice.(A, C) Temporal pattern of DAex before and after s.c. saline (Sal) or PCP (3 mg/kg) injection. The arrows indicate the drug injection time. Each point represents the mean ± SEM of the percentage of DAex baseline. (B, D) Histogram representing the mean AUC ± SEM of DAex during the 180 min period after saline or PCP injection (n = 5–11). ***p<0.001, compared with saline group of the same genotype; #p<0.05, ##p<0.01, comparisons between genotypes in the same drug treatment (two-way ANOVA followed by Fisher's PLSD post hoc test).

Mentions: Phencyclidine (3 mg/kg) markedly increased DAex in wildtype and GluRε1−/− mice, but not in GluRε4−/− mice, in the striatum and PFC (Fig. 2A, C). Two-way ANOVA (drug × genotype) of AUC values revealed a significant effect of drug (F1,39 = 17.201, p<0.001) but not genotype (F2,39 = 2.012, p = 0.147) in the striatum and a significant drug × genotype interaction (F2,39 = 3.314, p = 0.047) (Fig. 2B). Post hoc comparisons revealed that the effect of PCP on DAex in GluRε4−/− mice was significantly less compared with wildtype and GluRε1−/− mice (p = 0.002 and 0.03, respectively; Fisher's Protected Least Significant Difference [PLSD] post hoc test) in the striatum (Fig. 2B). In the PFC, two-way ANOVA (drug × genotype) of AUC values revealed a significant effect of drug (F1,37 = 35.215, p<0.001) but not genotype (F2,37 = 1.969, p = 0.154) and a significant drug × genotype interaction (F2,37 = 3.326, p = 0.047) (Fig. 2D). Post hoc comparisons revealed that the effect of PCP on DAex in GluRε4−/− mice was significantly less compared with wildtype and GluRε1−/− mice (p = 0.007 and 0.003, respectively; Fisher's PLSD post hoc test) in the PFC (Fig. 2D).


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)

Effects of acute PCP on DAex in the striatum and PFC in wildtype, GluRε1−/−, and GluRε4−/− mice.(A, C) Temporal pattern of DAex before and after s.c. saline (Sal) or PCP (3 mg/kg) injection. The arrows indicate the drug injection time. Each point represents the mean ± SEM of the percentage of DAex baseline. (B, D) Histogram representing the mean AUC ± SEM of DAex during the 180 min period after saline or PCP injection (n = 5–11). ***p<0.001, compared with saline group of the same genotype; #p<0.05, ##p<0.01, comparisons between genotypes in the same drug treatment (two-way ANOVA followed by Fisher's PLSD post hoc test).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2965660&req=5

pone-0013722-g002: Effects of acute PCP on DAex in the striatum and PFC in wildtype, GluRε1−/−, and GluRε4−/− mice.(A, C) Temporal pattern of DAex before and after s.c. saline (Sal) or PCP (3 mg/kg) injection. The arrows indicate the drug injection time. Each point represents the mean ± SEM of the percentage of DAex baseline. (B, D) Histogram representing the mean AUC ± SEM of DAex during the 180 min period after saline or PCP injection (n = 5–11). ***p<0.001, compared with saline group of the same genotype; #p<0.05, ##p<0.01, comparisons between genotypes in the same drug treatment (two-way ANOVA followed by Fisher's PLSD post hoc test).
Mentions: Phencyclidine (3 mg/kg) markedly increased DAex in wildtype and GluRε1−/− mice, but not in GluRε4−/− mice, in the striatum and PFC (Fig. 2A, C). Two-way ANOVA (drug × genotype) of AUC values revealed a significant effect of drug (F1,39 = 17.201, p<0.001) but not genotype (F2,39 = 2.012, p = 0.147) in the striatum and a significant drug × genotype interaction (F2,39 = 3.314, p = 0.047) (Fig. 2B). Post hoc comparisons revealed that the effect of PCP on DAex in GluRε4−/− mice was significantly less compared with wildtype and GluRε1−/− mice (p = 0.002 and 0.03, respectively; Fisher's Protected Least Significant Difference [PLSD] post hoc test) in the striatum (Fig. 2B). In the PFC, two-way ANOVA (drug × genotype) of AUC values revealed a significant effect of drug (F1,37 = 35.215, p<0.001) but not genotype (F2,37 = 1.969, p = 0.154) and a significant drug × genotype interaction (F2,37 = 3.326, p = 0.047) (Fig. 2D). Post hoc comparisons revealed that the effect of PCP on DAex in GluRε4−/− mice was significantly less compared with wildtype and GluRε1−/− mice (p = 0.007 and 0.003, respectively; Fisher's PLSD post hoc test) in the PFC (Fig. 2D).

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