Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure

Wang, Xun; Gu, Zhenglin; Zhong, Ping; Chen, Guojun; Feng, Jian; Yan, Zhen

doi:10.1016/j.mcn.2005.08.018

Cited by 15 publications

(16 citation statements)

References 64 publications

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“…This effect of PCP treatment on 5-HT 1A signaling is unique and differs from that on dopamine signaling. We have found that rats exposed to PCP show attenuated D 4 inhibition of NMDAR current as a result of the loss of D 4 regulation of Ca 2ϩ /camodulin-dependent protein kinase II and unchanged D 1 enhancement of NMDAR current (Wang et al, 2006). Levels of RGS proteins or mRNAs are tightly regulated by neuronal stimuli, which provides an important mechanism for influencing GPCR signaling pathways (Burchett et al, 1998;Ingi et al, 1998).…”

Section: Discussionmentioning

confidence: 97%

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RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

Jiang²,

Yan³

2007

Mol Pharmacol

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Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia remain largely unknown. In this study, we investigated the possible impact of RGS4 on the function of serotonin and dopamine receptors, two main targets for schizophrenia treatment. Activation of serotonin 5-HT 1A receptors or dopamine D 4 receptors down-regulates the function of NMDA receptor (NMDAR) channel, a key player controlling cognition and emotion, in pyramidal neurons of prefrontal cortex (PFC). Blocking RGS4 function significantly potentiated the 5-HT 1A regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT 1A effect. In contrast, the D 4 regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT 1A regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells. Thus, our study has revealed an important coupling of RGS4 to serotonin signaling in cortical neurons and provided a molecular and cellular mechanism underlying the potential involvement of RGS4 in the pathophysiology of schizophrenia.

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Section: Discussionmentioning

confidence: 97%

“…The rat PCP model of schizophrenia was generated as we reported recently (Wang et al, 2006). In brief, PCP (Sigma, St. Louis, MO) was administered at a dose of 3 mg/kg in sterile saline.…”

Section: Methodsmentioning

confidence: 99%

RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

Jiang²,

Yan³

2007

Mol Pharmacol

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“…Some of the atypical APDs that reverse the effects of PCP have D 3 and D 4 receptor affinities that might possibly contribute to their efficacy even at the subthreshold dose (see Table 1 for K i values). Wang et al (2006) reported that 3 days of treatment with PCP, as well as acute PCP, impaired D 4 receptor modulation of NMDA receptors and D 4 regulation of Ca 2ϩ /calmodulin-dependent kinase II activity. The effect of PCP on D 4 -mediated stimulation of NMDA receptors was reversed by clozapine (Wang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Wang et al (2006) reported that 3 days of treatment with PCP, as well as acute PCP, impaired D 4 receptor modulation of NMDA receptors and D 4 regulation of Ca 2ϩ /calmodulin-dependent kinase II activity. The effect of PCP on D 4 -mediated stimulation of NMDA receptors was reversed by clozapine (Wang et al, 2006). It is possible that the atypical APDs do not use the same mechanisms to potentiate 5-HT 2A and D 2 receptor blockade to reverse the NOR impairment due to PCP.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine_2A Receptor Inverse Agonist

Snigdha

Horiguchi

Huang

et al. 2009

J Pharmacol Exp Ther

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Subchronic administration of the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT 2A inverse agonists, pimavanserin and, would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05-0.1 mg/kg), melperone (1-3 mg/kg), olanzapine (1-2 mg/kg), or N-desmethylclozapine (1-2 mg/kg), and the typical APD, haloperidol (0.05-0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial (p Ͻ 0.05-0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine 2A receptor blockade relative to D 2 receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia.

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“…In some experiments, PCP (Sigma) was administered (5 mg/kg i.p.) once daily for 7 days (Wang et al, 2006). One day after the last administration of PCP, animals were injected with lurasidone (0.1 mg/kg s.c.) or clozapine (5 mg/kg s.c.) and sacrificed 1 h later.…”

Section: Animalsmentioning

confidence: 99%

The Novel Antipsychotic Drug Lurasidone Enhances N-Methyl-d-aspartate Receptor-Mediated Synaptic Responses

Yuen

Wei

et al. 2011

Mol Pharmacol

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N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunctionhas been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors and dopamine D 2 receptors. In vivo administration of the 5-HT 7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D 2 receptor antagonist haloperidol failed to do so. Previous studies have found that shortterm administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT 7 receptors, which is consistent with evidence that 5-HT 7 receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.

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Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure

Cited by 15 publications

References 64 publications

RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine_2A Receptor Inverse Agonist

The Novel Antipsychotic Drug Lurasidone Enhances N-Methyl-d-aspartate Receptor-Mediated Synaptic Responses

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Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure

Cited by 15 publications

References 64 publications

RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine2A Receptor Inverse Agonist

The Novel Antipsychotic Drug Lurasidone Enhances N-Methyl-d-aspartate Receptor-Mediated Synaptic Responses

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Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine_2A Receptor Inverse Agonist