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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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Related in: MedlinePlus

Effects of acute METH and PCP on the locomotor activity in GluRε1−/− and GluRε4−/− mice.Locomotor activity after acute saline, METH (1 mg/kg), or PCP (3 mg/kg) administration (n = 10–25). *p<0.05, **p<0.01, compared with saline (Student's t-test); #p<0.05, ##p<0.01, compared with wildtype (Student's t-test).
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pone-0013722-g004: Effects of acute METH and PCP on the locomotor activity in GluRε1−/− and GluRε4−/− mice.Locomotor activity after acute saline, METH (1 mg/kg), or PCP (3 mg/kg) administration (n = 10–25). *p<0.05, **p<0.01, compared with saline (Student's t-test); #p<0.05, ##p<0.01, compared with wildtype (Student's t-test).

Mentions: Two-way ANOVA (drug × genotype) of locomotor activity data during the 60 min period revealed significant effects of drug (F2,155 = 8.646, p = 0.0002) and genotype (F2,155 = 11.769, p<0.0001) and a significant drug × genotype interaction (F4,155 = 5.734, p = 0.0002) (Fig. 4). Methamphetamine (1 mg/kg) significantly increased locomotor activity during the 60 min period after the METH injection in wildtype mice (p = 0.002, Student's t-test) and GluRε4−/− mice (p = 0.0004, Student's t-test) compared with saline. However, METH (1 mg/kg) did not increase locomotor activity during the 60 min period after the METH injection in GluRε1−/− mice (p = 0.411, Student's t-test) compared with saline.


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 METH and PCP on the locomotor activity in GluRε1−/− and GluRε4−/− mice.Locomotor activity after acute saline, METH (1 mg/kg), or PCP (3 mg/kg) administration (n = 10–25). *p<0.05, **p<0.01, compared with saline (Student's t-test); #p<0.05, ##p<0.01, compared with wildtype (Student's t-test).
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Related In: Results  -  Collection

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

pone-0013722-g004: Effects of acute METH and PCP on the locomotor activity in GluRε1−/− and GluRε4−/− mice.Locomotor activity after acute saline, METH (1 mg/kg), or PCP (3 mg/kg) administration (n = 10–25). *p<0.05, **p<0.01, compared with saline (Student's t-test); #p<0.05, ##p<0.01, compared with wildtype (Student's t-test).
Mentions: Two-way ANOVA (drug × genotype) of locomotor activity data during the 60 min period revealed significant effects of drug (F2,155 = 8.646, p = 0.0002) and genotype (F2,155 = 11.769, p<0.0001) and a significant drug × genotype interaction (F4,155 = 5.734, p = 0.0002) (Fig. 4). Methamphetamine (1 mg/kg) significantly increased locomotor activity during the 60 min period after the METH injection in wildtype mice (p = 0.002, Student's t-test) and GluRε4−/− mice (p = 0.0004, Student's t-test) compared with saline. However, METH (1 mg/kg) did not increase locomotor activity during the 60 min period after the METH injection in GluRε1−/− mice (p = 0.411, Student's t-test) compared with saline.

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