Decreased serotonin2C receptor responses in male patients with schizophrenia

Lee, Myung Ae; Jayathilake, Karuna; Sim, Min Young; Meltzer, Herbert Y.

doi:10.1016/j.psychres.2015.01.007

Cited by 6 publications

(4 citation statements)

References 72 publications

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“…Lorcaserin is the first-in-class 5-HT 2C agonist that has won FDA approval in 2012 for the treatment of obesity, and a clinical trial to evaluate its use in smoking cessation has also been completed, with the results remaining to be disclosed . Vabicaserin was studied in clinical trials for the treatment of acute schizophrenia, in which it demonstrated significant therapeutic effects and achieved a proof-of-concept, but it failed to meet the primary efficacy objective. , For many years it has been appreciated that 5-HT 2C receptor function might be altered in schizophrenia and that the 5-HT 2C antagonist activity of certain atypical antipsychotic drugs might be associated with weight gain and adverse metabolic consequences. − Advantages of the 5-HT 2C receptor as a drug target for treating schizophrenia and related disorders include the following: (1) activation of 5-HT 2C receptors specifically decreases mesolimbic dopamine release without affecting nigrostriatal dopamine; thus, it is predicted to have antipsychotic efficacy while causing few extrapyramidal symptoms (EPS); (2) 5-HT 2C agonists are known to induce weight loss, and thus such drugs should lack the undesired side effect of weight gain and related metabolic disorders, which have been associated with most current antipsychotic drugs. , Additionally, activation of the 5-HT 2C receptor has been demonstrated to counter cognitive deficits induced by N -methyl- d -aspartate (NMDA) antagonism, as well as to overcome cognitive deficits in animals bearing the human tryptophan hydroxylase 2 (Tph2) loss of function mutation . Therefore, developing safe 5-HT 2C agonists for the treatment of schizophrenia could potentially address the cognitive deficits associated with this disease with fewer EPS and a lower risk of causing weight gain.…”

Section: Introductionmentioning

confidence: 99%

Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models

et al. 2016

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A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models

et al. 2016

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“…SNORD115 shares sequence complementarity with ExonVb of the serotonin 2C receptor (HTR2C) transcript, and is thought to modulate alternative splicing of HTR2C [ 87 ]. While decreased HTR2C levels and function have been reported in subjects with schizophrenia [ 91 , 92 ], there does not appear to be any evidence of altered RNA editing of HTR2C in the CNS of subjects with schizophrenia [ 93 , 94 ]. Rodent studies suggest both SNORD115 and SNORD116 appear to be involved in memory consolidation during fear-based contextual learning, and thus they may contribute to the cognitive deficits in schizophrenia [ 95 , 96 ].…”

Section: Short Non-coding Rna In Schizophreniamentioning

confidence: 99%

Non-Coding RNA as Novel Players in the Pathophysiology of Schizophrenia

Gibbons

Udawela

Dean

2018

ncRNA

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Schizophrenia is associated with diverse changes in the brain’s transcriptome and proteome. Underlying these changes is the complex dysregulation of gene expression and protein production that varies both spatially across brain regions and temporally with the progression of the illness. The growing body of literature showing changes in non-coding RNA in individuals with schizophrenia offers new insights into the mechanisms causing this dysregulation. A large number of studies have reported that the expression of microRNA (miRNA) is altered in the brains of individuals with schizophrenia. This evidence is complemented by findings that single nucleotide polymorphisms (SNPs) in miRNA host gene sequences can confer an increased risk of developing the disorder. Additionally, recent evidence suggests the expression of other non-coding RNAs, such as small nucleolar RNA and long non-coding RNA, may also be affected in schizophrenia. Understanding how these changes in non-coding RNAs contribute to the development and progression of schizophrenia offers potential avenues for the better treatment and diagnosis of the disorder. This review will focus on the evidence supporting the involvement of non-coding RNA in schizophrenia and its therapeutic potential.

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“…mice with knocked out HTR2C are hyper-responsive to repeated stress [Chou-Green… 2003]; (d). male humans with schizophrenia are characterized by a decreased expression of HTRC2 functions [Lee… 2015]. These findings together suggest that the elevated expression of the HTRC2 gene in tame foxes is responsible for the increased comfort and easily -adaptable behavior of these animals, thus allowing them to become more receptive to interactions with humans.…”

Section: Lonely Neanderthal: In Quest Of Neurochemical Balancementioning

confidence: 99%

The Lonely Neanderthal: A Neurochemical Hypothesis for the Domestication of Animals and Plants

Tevzadze¹,

Kikvidze²,

Mikeladze³

et al. 2015

Kadmos

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Domestication in essence represents a set of human interactions with other species, in which behavior has a leading role. At the same time, recent findings from neurochemical research highlight the importance of an opioid system for such interactions. A combination of these neurochemical mechanisms and the peculiar social behavior of Neanderthal males could facilitate interactions between humans and wild species, and this type of behavior could be adopted by our ancestors in Eurasia from Neanderthals. These facilitative interactions could later lead to domestications. We propose that domestication is an artificial, social, and personal system of the repeated use of results gained from the behavior and existence of specific representatives of animal and plant species, often obtained by means of genetic selection, with the initial aim of producing a greater amount of endogenous opioids and related neurohormones in the human organism. The new perspective can help generate empirically testable predictions. First, it predicts that interactions with plants, similar to interactions with animals, will launch a cascade of neurochemical changes in the opioid system and establish certain patterns of our behavior; this prediction can be tested with the same experimental approach as used in the case of animals. Second, significant differences can be found in the ethnographical records between the shaman sub-cultures of Africa and Eurasia regarding the interactions with animals.

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Decreased serotonin2C receptor responses in male patients with schizophrenia

Cited by 6 publications

References 72 publications

Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models

Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models

Non-Coding RNA as Novel Players in the Pathophysiology of Schizophrenia

The Lonely Neanderthal: A Neurochemical Hypothesis for the Domestication of Animals and Plants

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