Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction

Thomson, David M.; Mitchell, Emma J.; Openshaw, Rebecca L.; Pratt, Judith A.; Morris, Brian J.

doi:10.1177/02698811211032439

Cited by 15 publications

(16 citation statements)

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“…An interesting thing was that several hub genes were involved in the neurological or psychiatric function or disorders such as CHRM4 [70,71], MTNR1B [72], and TAS2R19 [73,74]. Just as reported, plentiful common proteins and biochemical characteristics were shared between the human brain and testis [75].…”

Section: Discussionmentioning

confidence: 84%

Unearthing of key genes driving the infertility risk of cryptorchidism via weighted gene co- expression network

Lao

Zhang

et al. 2022

Preprint

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Background: Boys with cryptorchidism are susceptible to infertility. However, there are few known molecular markers of cryptorchidism-related infertility. Potential genes and molecular pathways to drive cryptorchidism-related infertility were investigated in this study via bioinformatics methods.Methods: Gene Expression Omnibus (GEO) database was utilized to download raw GSE25518 (training set) and GSE16191 (validation set) datasets. GSE25518 was used for differentially expressed genes (DEGs) identification and weighted gene co-expression network analysis (WGCNA). Hub genes were identified from the intersection of key genes from DEGs and the key module in WGCNA. Hub genes’ expression differences and diagnostic value were subsequently verified via GSE16191. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene set enrichment analysis (GSEA) were deployed for functional annotation.Results: 761 definitive DEGs were identified while 12 hub genes (CHRM4, CCR4, LMNB1, MTNR1B, TAC3, TRHR, RAD54L, CCNA1, SMC1B, GPRC6A, SYCE2, TAS2R19) were identified finally. The hub genes were also differentially expressed and showed excellent diagnostic value to distinguish cryptorchidism from normal testes in GSE16191. Additionally, they were well correlated with genes from the hallmark_spermatogenesis gene set. And they might be involved in oxidative phosphorylation, MYC targets V1, cholesterol homeostasis, KRAS activation, etc. Hallmark_spermatogenesis gene set was significantly enriched by five hub genes (RAD54L, CCNA1, SMC1B, TAC3, MTNR1B).Conclusion: We have identified 12 genes that might become new biomarkers for cryptorchidism-related infertility while five genes (RAD54L, CCNA1, SMC1B, TAC3, MTNR1B) deserve more attention.

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Section: Discussionmentioning

confidence: 84%

Unearthing of key genes driving the infertility risk of cryptorchidism via weighted gene co- expression network

Lao

Zhang

et al. 2022

Preprint

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“… 159 An alternative approach, highlighted by work in rodents, would be fMRI and electroencephalographic strategies for exploring circuits involved in the relief of GAD by agomelatine in comparison to other classes of agent. 85 , 108 , 112 , 160 …”

Section: General Discussion: Open Questions and Perspectivesmentioning

confidence: 99%

“… 102 In line with this work, male and/or female mice genetically deprived of MT 2 receptors display enhanced anxiety. 105 – 108 As regards human subjects, data are very sparse, yet there is fragmentary evidence for anxiolytic effects of MT under specific conditions, such as pre-operative stress. 100 , 109 …”

Section: A Complementary Role For Mt Receptors In the Anxiolytic Acti...mentioning

confidence: 99%

“…Accordingly, it has been proposed that activation of MT 2 receptors in the TRN acts via this neural cascade to counter anxiety, and they are a potential substrate for the anxiolytic actions of agomelatine. 102 , 108 , 125 This possibility is especially interesting bearing in mind the role of the TRN in sleep 126 and evidence that agomelatine influences the activity of neurons in the dorsomedial thalamus and FCX downstream of the TRN. 23 , 112 Finally, a role of either MT 1 and/or MT 2 receptors in the hippocampus may, by analogy to their 5-HT 2C counterparts, be involved in the response to stress and the anxiolytic actions of MT together with, by extrapolation, agomelatine.…”

Section: Cerebral Loci Of Action Of Agomelatine In Relation To Fear-a...mentioning

confidence: 99%

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Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action

Millan

2022

Therapeutic Advances in Psychopharmacology

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Generalized anxiety disorder (GAD), the most frequently diagnosed form of anxiety, is usually treated by cognitive-behavioural approaches or medication; in particular, benzodiazepines (acutely) and serotonin or serotonin/noradrenaline reuptake inhibitors (long term). Efficacy, compliance, and acceptability are, however, far from ideal, reinforcing interest in alternative options. Agomelatine, clinically employed in the treatment of major depression, expresses anxiolytic properties in rodents and was effective in the treatment of GAD (including severely ill patients) in several double-blind, short-term (12 weeks) and relapse-prevention (6 months) studies. At active doses, the incidence of adverse effects was no higher than for placebo. Agomelatine possesses a unique binding profile, behaving as a melatonin (MT1/MT2) receptor agonist and 5-HT2C receptor antagonist, yet recognizing neither monoamine transporters nor GABAA receptors. Extensive evidence supports a role for 5-HT2C receptors in the induction of anxious states, and their blockade likely plays a primary role in mediating the anxiolytic actions of agomelatine, including populations in the amygdala and bed nucleus of stria terminalis, as well as the hippocampus. Recruitment of MT receptors in the suprachiasmatic nucleus, thalamic reticular nucleus, and hippocampus appears to fulfil a complimentary role. Downstream of 5-HT2C and MT receptors, modulation of stress-sensitive glutamatergic circuits and altered release of the anxiogenic neuropeptides, corticotrophin-releasing factor, and vasopressin, may be implicated in the actions of agomelatine. To summarize, agomelatine exerts its anxiolytic actions by mechanisms clearly distinct from those of other agents currently employed for the management of GAD. Plain Language Summary How agomelatine helps in the treatment of anxiety disorders Introduction: • Anxiety disorders have a significant negative impact on quality of life. • The most common type of anxiety disorder, called generalized anxiety disorder (GAD), is associated with nervousness and excessive worry. • These symptoms can lead to additional symptoms like tiredness, sleeplessness, irritability, and poor attention. • GAD is generally treated through either cognitive-behavioural therapy or medication. However, widely used drugs like benzodiazepines and serotonin reuptake inhibitors have adverse effects. • Agomelatine, a well-established antidepressant drug, has shown anxiety-lowering (‘anxiolytic’) properties in rats and has been shown to effectively treat GAD with minimal side effects. • However, exactly how it acts on the brain to manage GAD is not yet clear. • Thus, this review aims to shed light on agomelatine’s mechanism of action in treating GAD. Methods: • The authors reviewed studies on how agomelatine treats anxiety in animals. • They also looked at clinical studies on the effects of agomelatine in people with GAD. Results: • The study showed that agomelatine ‘blocks’ a receptor in nerve cells, which plays a role in causing anxiety, called the 5-HT2C receptor. • Blocking this receptor, especially in specific brain regions such as nerve cells of the amygdala, bed nucleus of stria terminalis, and hippocampus, produced the anxiety reduction seen during agomelatine treatment. • Agomelatine also activates the melatonin (MT) receptor, which is known to keep anxiety in check, promote sleep, and maintain the sleep cycle. • Agomelatine should thus tackle sleep disturbances commonly seen in patients with GAD. • Beyond 5-HT2C and MT receptors, signalling molecules in nerve cells that are known to be involved in anxiety disorders (called ‘neurotransmitters’ and ‘neuropeptides’) are also affected by agomelatine. Conclusion: • Agomelatine’s anxiolytic effects are caused by mechanisms that are distinct from those of other medications currently used to treat GAD. • This explains its therapeutic success and minimal adverse side effects.

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“…They found that the MT2 receptor plays a role in cognition and modulates anxiety and social interactions. Their data provide useful insights into the functions of endogenous melatonin, which may help to inform future drug development strategies focussed on the MT2 receptor (Thomson et al, 2021).…”

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confidence: 99%

Translational psychopharmacology

Young

2021

J Psychopharmacol

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Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction

Cited by 15 publications

References 83 publications

Unearthing of key genes driving the infertility risk of cryptorchidism via weighted gene co- expression network

Unearthing of key genes driving the infertility risk of cryptorchidism via weighted gene co- expression network

Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action

Translational psychopharmacology

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