The Role of 5-Hydroxytryptamine 7 Receptors in the Phencyclidine-Induced Novel Object Recognition Deficit in Rats

Horiguchi, Masaaki; Huang, Mei; Meltzer, Herbert Y.

doi:10.1124/jpet.111.180638

Cited by 120 publications

(87 citation statements)

References 46 publications

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“…A growing body of evidence supports the concept for targeting 5-HT 7 antagonism as a possible mechanism for the treatment of cognitive deficits and a potential target for novel anxiolytic and antidepressant drugs (Hedlund et al, 2005;Abbas et al, 2009;Mnie-Filali et al, 2009;Horiguchi et al, 2011). In conclusion, the results reported here suggest that the procognitive effect of 5-HT 7 receptor antagonism (Gasbarri et al, 2008;Horiguchi et al, 2011) may result from enhancement of NMDAR function.…”

Section: Discussionsupporting

confidence: 56%

“…The electrophysiological results reported here are consistent with the behavioral effects of these compounds in schizophrenia models. Horiguchi et al (2011) have found that lurasidone, clozapine, and SB-269970, but not haloperidol, improve the impairment in NOR induced by subchronic PCP treatment. Moreover, the ability of lurasidone to reverse the PCP-induced NOR deficit is blocked by the 5-HT 7 agonist AS19 (Horiguchi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the ability of lurasidone and clozapine to improve cognition in animal models of schizophrenia (Ishiyama et al, 2007;Enomoto et al, 2008;Nakamura et al, 2009;Snigdha et al, 2010;Horiguchi et al, 2011), little is known about the molecular and cellular mechanism underlying this action. Repeated exposure to lurasidone increases the mRNA and protein levels of brain-derived neurotrophic factor (Fumagalli et al, 2011), an important determinant of synaptic plasticity of glutamatergic synapses, consistent with the idea that antipsychotic treatment may change the expression, trafficking, and interaction of essential components of glutamatergic synapses (Fumagalli et al, 2008;Iasevoli et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Because lurasidone reversed the effect of subchronic PCP administration on novel object recognition (Horiguchi et al, 2011) and was shown here to potently increase NMDAR function, we further tested its ability to restore NMDAR hypofunction in PCP-treated rats. Thus, we administered lurasidone after subchronic treatment of PCP (5 mg/kg i.p., 7 days).…”

Section: In Vivo Administration Of Lurasidone Induces a Significant Ementioning

confidence: 99%

“…Clinical trials have shown that lurasidone is a safe and effective treatment for patients with schizophrenia and has minimal extrapyramidal, cardiovascular, and metabolic complications (Nakamura et al, 2009;Citrome, 2011;Meltzer et al, 2011a). Lurasidone has been reported to improve short-term MK-801-induced memory impairment in rats (Ishiyama et al, 2007;Enomoto et al, 2008), as well as subchronic PCP-induced impairment in novel object recognition (NOR) (Horiguchi et al, 2011;Meltzer et al, 2011b). The molecular mechanism for the atypical APDs to improve cognition is not fully known.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: In Vivo Administration Of Lurasidone Induces a Significant Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Metabotropic Glutamate Receptors for New Treatments in Schizophrenia

Herman

Bubser

Conn

et al. 2012

Handbook of Experimental Pharmacology

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Metabotropic glutamate receptors (mGluRs) represent exciting targets for the development of novel therapeutic agents for schizophrenia. Recent studies indicate that selective activation of specific mGluR subtypes may provide potential benefits for not only the positive symptoms, but also the negative symptoms and cognitive impairments observed in individuals with schizophrenia. Although optimization of traditional orthosteric agonists may still offer a feasible approach for the activation of mGluRs, important progress has been made in the discovery of novel subtype-selective allosteric ligands, including positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These allosteric mGluR ligands have improved properties for clinical development and have served as key preclinical tools for a more in-depth understanding of the potential roles of these different mGluR subtypes for the treatment of schizophrenia.

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Serotonergic Mechanisms as Targets for Existing and Novel Antipsychotics

Meltzer

2012

Handbook of Experimental Pharmacology

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A variety of serotonin (5-HT) receptors, especially 5-HT(2A), 5-HT(1A), 5-HT(6), 5-HT(7), and 5-HT(2C), have been postulated to contribute to the mechanism of action of atypical antipsychotic drugs (APDs), i.e., APDs which cause fewer extrapyramidal side effects (EPS) at clinically optimal doses, in contrast with typical APDs, which are more likely to cause EPS. This advantage, rarely disputed, has made such drugs the preferred treatment for schizophrenia and other indications for APDs. These 5-HT receptors are still of interest as components of novel multireceptor or stand-alone APDs, and potentially to remediate cognitive deficits in schizophrenia. Almost all currently available atypical APDs are 5-HT(2A) receptor inverse agonists, as well as dopamine (DA) D(2) receptor antagonists or partial agonists. Amisulpride, an exceptional atypical APD, has 5-HT(7) antagonism to complement its DA D(2/3) antagonism. Some atypical APDs are also 5-HT(1A) partial agonists, 5-HT(6), or 5-HT(7) antagonists, or some combination of the above. 5-HT(2C) antagonism has been found to contribute to the metabolic side effects of some atypical APDs, whereas 5-HT(2C) agonists have potential as stand-alone APDs and/or cognitive enhancers. This review will provide an update of current preclinical and clinical evidence for the role of these five 5-HT receptors in the actions of current APDs and for the development of novel psychotropic drugs.

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The Role of 5-Hydroxytryptamine 7 Receptors in the Phencyclidine-Induced Novel Object Recognition Deficit in Rats

Cited by 120 publications

References 46 publications

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

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

Metabotropic Glutamate Receptors for New Treatments in Schizophrenia

Serotonergic Mechanisms as Targets for Existing and Novel Antipsychotics

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