The selective 5-HT1A receptor agonist NLX-112 displays anxiolytic-like activity in mice

Powell, William; Annett, L. E.; Depoortère, R.; Newman‐Tancredi, Adrian; Iravani, Mahmoud M.

doi:10.1007/s00210-021-02183-2

Cited by 6 publications

(7 citation statements)

References 48 publications

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“…To further clarify this Ec -LPS-induced inhibition of locomotor activity, more detailed analysis indicated this inhibition to be evident similarly in both the peripheral and central zones of the open field. As anxiety- and/or depression-related processes are reflected in differential effects between these zones [23], such processes are not implicated in the present findings. Rather, they may reflect evidence that LPS-induced reductions in locomotor activity, including spatial exploration, relate to prevention of the spread of inflammation and promotion of healing [16].…”

Section: Discussionmentioning

confidence: 67%

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Lipopolysaccharides derived fromPorphyromonas gingivalisandEscherichia coli:differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TRL4-related processes

Saito,

Aono,

Watanabe

et al. 2023

Preprint

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Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, activates Toll-like receptors (TLRs).Porphyromonas gingivalis(Pg) may be involved in the progression of periodontal disease. Mice exposed to a novel environment show hyperlocomotion that is inhibited by systemic administration of LPS derived fromEscherichia coli(Ec-LPS). However, whetherPg-LPS influences novelty-induced locomotion is unknown. Accordingly, we carried out an open field test to analyse the effects ofPg-LPS. For comparison, effects ofEc-LPS were also studied. We also investigated the influence of systemic administration ofPg-LPS orEc-LPS on IL-6, TNF-alpha, and IL-10 levels in blood, as they could be involved in the changes in locomotion. The TLR4 receptor antagonist TAK-242 was used to study the involvement of TLR4. SincePg-LPS may block TLR4in vitro, we analysed the effects ofPg-LPS onEc-LPS-induced changes in behavioural and biochemical parameters. Male ddY mice were used. Compounds were administered intraperitoneally.Ec-LPS (840 µg/kg), but notPg-LPS (100, 500 and 840 µg/kg), inhibited novelty-induced locomotion, which was reversed by TAK-242 (3.0 mg/kg).Ec-LPS (840 µg/kg) increased blood levels of IL-6 and IL-10, which was antagonized by TAK-242 (3.0 mg/kg). However, TAK-242 did not inhibitEc-LPS-induced increases in TNF-alpha levels in blood.Pg-LPS (100, 500, and 840 µg/kg) did not alter blood IL-6, TNF-alpha, or IL-10 levels. TheEc-LPS-induced increase in blood IL-10, but not IL-6 and TNF-alpha, levels was inhibited byPg-LPS (500 µg/kg). These results suggest that TLR4 stimulation mediates the inhibition of novel environment-induced locomotion in mice following systemic administration ofEc-LPS, while also increasing blood IL-6 and IL-10 levels. In contrast,Pg-LPS did not exhibit these effects. The present study also providesin vivoevidence thatPg-LPS can inhibit TLR4-mediated increases in blood IL-10 levels, which is thought to prevent the development of periodontal disease.

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Section: Discussionmentioning

confidence: 67%

“…As differential effects on locomotion in the peripheral vs central zones of the open field implicate anxiety-/depression-related processes [23], we analyzed the effects of Ec -LPS (840 µg/kg) on locomotion in these two zones. Ec -LPS treatment inhibited locomotion in both the central and peripheral zones (Fig.…”

Section: Resultsmentioning

confidence: 99%

Lipopolysaccharides derived fromPorphyromonas gingivalisandEscherichia coli:differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TRL4-related processes

Saito,

Aono,

Watanabe

et al. 2023

Preprint

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“…As differential effects on locomotion in the peripheral vs central zones of the open field implicate anxiety-/depression-related processes [ 31 ], we analyzed the effects of Ec -LPS (840 μg/kg) on locomotion in these two zones. Ec -LPS treatment inhibited locomotion in both the central and peripheral zones ( Fig 3 : Student’s t -tests, Ec -LPS 840 μg/kg vs vehicle: central zone: t (12) = 2.19, P < 0.05; peripheral zone: t (12) = 3.93, P < 0.01).…”

Section: Resultsmentioning

confidence: 99%

Lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli: Differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TLR4-related processes

Aono,

Saito,

Kawashima

et al. 2024

PLoS ONE

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Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, activates Toll-like receptors (TLRs). Porphyromonas gingivalis (Pg) may be involved in the progression of periodontal disease. Mice exposed to a novel environment show hyperlocomotion that is inhibited by systemic administration of LPS derived from Escherichia coli (Ec-LPS). However, whether Pg-LPS influences novelty-induced locomotion is unknown. Accordingly, we carried out an open field test to analyse the effects of Pg-LPS. For comparison, effects of Ec-LPS were also studied. We additionally investigated the influence of systemic administration of Pg-LPS or Ec-LPS on IL-6, TNF-alpha, and IL-10 levels in blood, as they could be involved in the changes in locomotion. The TLR4 receptor antagonist TAK-242 was used to study the involvement of TLR4. Since Pg-LPS may block TLR4 in vitro, we analysed the effects of Pg-LPS on Ec-LPS-induced changes in behavioural and biochemical parameters. Male ddY mice were used. Pg- or Ec-LPS and TAK-242 were administered intraperitoneally. Ec-LPS (840 μg/kg), but not Pg-LPS (100, 500 and 840 μg/kg), inhibited novelty-induced locomotion, which was antagonized by TAK-242 (3.0 mg/kg). Ec-LPS (840 μg/kg) increased blood levels of IL-6 and IL-10, which were antagonized by TAK-242 (3.0 mg/kg). However, TAK-242 did not inhibit Ec-LPS-induced increases in TNF-alpha levels in blood. Pg-LPS (100, 500, and 840 μg/kg) did not alter blood IL-6, TNF-alpha, or IL-10 levels. The Ec-LPS-induced increase in blood IL-10, but not IL-6 and TNF-alpha, levels was inhibited by Pg-LPS (500 μg/kg). These results suggest that TLR4 stimulation mediates the inhibition of novel environment-induced locomotion in mice following systemic administration of Ec-LPS, while also increasing blood IL-6 and IL-10 levels. In contrast, Pg-LPS did not exhibit these effects. The present study also provides in vivo evidence that Pg-LPS can inhibit TLR4-mediated increases in blood levels of IL-10, a cytokine thought to prevent the development of periodontal disease.

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“…A more detailed study of different signaling pathways is needed in order to fully characterize the activity spectra of this variant. Recent studies suggested that the differential effects of 5-HT 1A receptors expressed at different synapses might be a result of activation of different signaling pathways ( Newman-Tancredi et al, 2022 ; Powell et al, 2022 ). Thus, identifying a biased variant of 5-HT 1A receptor could lead to a continuing in vivo studies aimed for better understanding of the differential roles of the 5-HT 1A receptor in the brain and their relation to psychiatric condition, such as depression.…”

Section: Discussionmentioning

confidence: 99%

“…5-HT receptors mediate many cellular processes ( Seyedabadi et al, 2014 ; Sharp and Barnes, 2020 ) and have been implicated in many brain disorders, including depression and anxiety ( Švob Štrac et al, 2016 ; Carhart-Harris and Nutt, 2017 ). 5-HT 1A receptor is the most abundant serotonin receptor and its ligands serve as pharmacological target for antidepressants and antipsychotic drug discovery ( Bantick et al, 2001 ; Newman-Tancredi, 2010 ; Powell et al, 2022 ; Yao et al, 2022 ). 5-HT 1A receptors regulate serotoninergic neurotransmission in serotoninergic neurons in the raphe nuclei where they serve as autoreceptors ( Lanfumey and Hamon, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Functional consequences of a rare human serotonergic 5-HT1A receptor variant

Tauber,

Ben-Chaim

2023

Front. Pharmacol.

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Serotonin (5-HT) plays a central role in various brain functions via the activation of a family of receptors, most of them G protein coupled receptors (GPCRs). 5-HT1A receptor, the most abundant 5-HT receptors, was implicated in many brain dysfunctions and is a major target for drug discovery. Several genetic polymorphisms within the 5-HT1A receptor gene were identified and linked to different conditions, including anxiety and depression. Here, we used Xenopus oocytes to examine the effects of one of the functional polymorphism, Arg220Leu, on the function of the receptor. We found that the mutated receptor shows normal activation of G protein and normal 5-HT binding. On the other hand, the mutated receptor shows impaired desensitization, probably due to impairment in activation of β arrestin-dependent pathway. Furthermore, while the 5-HT1A receptor was shown to exhibit voltage dependent activation by serotonin and by buspirone, the mutated receptor was voltage-independent. Our results suggest a pronounced effect of the mutation on the function of the 5-HT1A receptor and add to our understanding of the molecular mechanism of its voltage dependence. Moreover, the findings of this study may suggest a functional explanation for the possible link between this variant and brain pathologies.

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The selective 5-HT1A receptor agonist NLX-112 displays anxiolytic-like activity in mice

Cited by 6 publications

References 48 publications

Lipopolysaccharides derived fromPorphyromonas gingivalisandEscherichia coli:differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TRL4-related processes

Lipopolysaccharides derived fromPorphyromonas gingivalisandEscherichia coli:differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TRL4-related processes

Lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli: Differential and interactive effects on novelty-induced hyperlocomotion, blood cytokine levels and TLR4-related processes

Functional consequences of a rare human serotonergic 5-HT1A receptor variant

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