Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats

An, Yan; Chen, Chong; Inoue, Takeshi; Nakagawa, Shin; Kitaichi, Yuji; Izumi, Tohru; Kusumi, Ichiro

doi:10.1016/j.pnpbp.2016.04.014

Cited by 16 publications

(10 citation statements)

References 47 publications

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“…Several meta-analyses also revealed that common structural and functional changes in brain circuits underlying emotion regulation ( Etkin and Schatzberg, 2011 ), executive function ( Goodkind et al, 2015 ), and cognitive control ( McTeague et al, 2017 ) in both anxiety and depression. Further, alterations in prefrontal limbic pathways ( Kovner et al, 2019 ; McTeague et al, 2020 ) and serotonergic projections arising from the raphe nuclei are associated with both depression and anxiety ( An et al, 2016 ). Moreover, depression is associated with a single nucleotide polymorphisms-heritability of 12–14 %, indicating substantial genetic overlap with anxiety ( Purves et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Network analysis of comorbid depression and anxiety and their associations with quality of life among clinicians in public hospitals during the late stage of the COVID-19 pandemic in China

Jin

Sha

Tian

et al. 2022

Journal of Affective Disorders

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Section: Discussionmentioning

confidence: 99%

Network analysis of comorbid depression and anxiety and their associations with quality of life among clinicians in public hospitals during the late stage of the COVID-19 pandemic in China

Jin

Sha

Tian

et al. 2022

Journal of Affective Disorders

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“…Several research studies have suggested that mirtazapine decreases anxiety-like behavior in the EPM and depression-like behaviors in the FST in animals treated with saline (An et al, 2013, 2015, 2016a, 2016b; Kaminska and Rogoz, 2016; Rogóż, 2010, 2012; Rogóż et al, 2012). We found similar results: in animals dosed with 30 mg mirtazapine, anxiety-like (as measured in the EPM test, OFT and the LDT) and depression-like behaviors (according to the FST) decreased after 15 days of treatment.…”

Section: Discussionmentioning

confidence: 99%

Mirtazapine attenuates anxiety- and depression-like behaviors in rats during cocaine withdrawal

Méndez

Salazar-Juárez

2019

J Psychopharmacol

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Background: Anxiety and depression, key symptoms of the cocaine withdrawal syndrome in human addicts, are considered the main factors that precipitate relapse in chronic cocaine addiction. Preclinical studies have found that rodents exposed to different withdrawal periods show an increase in anxiety and depressive-like behavior. Mirtazapine – a tetracyclic medication – is used primarily to treat depression and, sometimes, anxiety. It has also successfully improved withdrawal symptoms in drug-dependent patients. Aim: This study sought to determine whether chronic dosing of mirtazapine during cocaine withdrawal reduced depression- and anxiety-like behaviors that characterize cocaine withdrawal in animals. Methods: Cocaine pre-treated Wistar rats were subjected to a 60-day cocaine withdrawal period during which depression- and anxiety-like behaviors were evaluated in open field tests (OFT), the elevated plus-maze (EPM), the light–dark box test (LDT), the forced swimming test (FST) and spontaneous locomotor activity (SLA). Results: We found that chronic dosing with different doses of mirtazapine (30 and 60 mg/kg) decreased depression- and anxiety-like behaviors induced by different doses of cocaine (10, 20 and 40 mg/kg) during the 60-day cocaine withdrawal. Interpretation: Our results suggest that the pharmacological effect of mirtazapine on its target sites of action (α2-adrenergic and 5-HT2A and 5-HT3 receptors) within the brain may improve depression- and anxiety-like behaviors for long periods. Conclusion: Therefore, the findings support the use of mirtazapine as a potentially effective therapy to reduce anxiety and depressive-like behavior during cocaine withdrawal.

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“…Given that 5-HT 1A has been implicated in both antiseizure [10] and learning-and-memory functions [22,23], we tested fenfluramine binding interaction with 5-HT 1A receptors. In 5-HT 1A assays, cellular dielectric spectroscopy measured impedance at 37°C after stimulation with 100 nM 8-OH-DPAT (antagonist assays) or 10 μM 8-OH-DPAT as a control (agonist assays).…”

Section: In Vitro Receptor Functional Activity Assaysmentioning

confidence: 99%

Fenfluramine acts as a positive modulator of sigma-1 receptors

Martin

Witte

Maurice

et al. 2020

Epilepsy & Behavior

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Adjunctive fenfluramine hydrochloride, classically described as acting pharmacologically through a serotonergic mechanism, has demonstrated a unique and robust clinical response profile with regard to its magnitude, consistency, and durability of effect on seizure activity in patients with pharmacoresistant Dravet syndrome. Recent findings also support long-term improvements in executive functions (behavior, emotion, cognition) in these patients. The observed clinical profile is inconsistent with serotonergic activity alone, as other serotonergic medications have not been demonstrated to have these clinical effects. This study investigated a potential role for σ 1 receptor activity in complementing fenfluramine's serotonergic pharmacology. Methods: Radioligand binding assays tested the affinity of fenfluramine for 47 receptors associated with seizures in the literature, including σ receptors. Cellular function assays tested fenfluramine and norfenfluramine (its major metabolite) activity at various receptors, including adrenergic, muscarinic, and serotonergic receptors. The σ 1 receptor activity was assessed by the mouse vas deferens isometric twitch and by an assay of dissociation of the σ 1 receptor from the endoplasmic reticulum stress protein binding immunoglobulin protein (BiP). In vivo mouse models assessed fenfluramine activity at σ 1 receptors in ameliorating dizocilpine-induced learning deficits in spatial and nonspatial memory tasks, alone or in combination with the reference σ 1 receptor agonist PRE-084. Results: Fenfluramine and norfenfluramine bound ≥30% to β 2 -adrenergic, muscarinic M 1 , serotonergic 5-HT 1A , and σ receptors, as well as sodium channels, with a K i between 266 nM (σ receptors) and 17.5 μM (β-adrenergic receptors). However, only σ 1 receptor isometric twitch assays showed a positive functional response, with weak stimulation by fenfluramine and inhibition by norfenfluramine. Fenfluramine, but not the 5-HT 2C agonist lorcaserin, showed a positive modulation of the PRE-084-induced dissociation of σ 1 protein from BiP. Fenfluramine also showed dose-dependent antiamnesic effects against dizocilpine-induced learning deficits in spontaneous alternation and passive avoidance responses, which are models of σ 1 activation. Moreover, low doses of fenfluramine synergistically potentiated the low-dose effect of PRE-084, confirming a positive modulatory effect at the σ 1 receptor. Finally, all in vivo effects were blocked by the σ 1 receptor antagonist NE-100. Significance: Fenfluramine demonstrated modulatory activity at σ 1 receptors in vitro and in vivo in addition to its known serotonergic activity. These studies identify a possible new σ 1 receptor mechanism underpinning fenfluramine's central nervous system effects, which may contribute to its antiseizure activity in Dravet syndrome and positive effects observed on executive functions in clinical studies.

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Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats

Cited by 16 publications

References 47 publications

Network analysis of comorbid depression and anxiety and their associations with quality of life among clinicians in public hospitals during the late stage of the COVID-19 pandemic in China

Network analysis of comorbid depression and anxiety and their associations with quality of life among clinicians in public hospitals during the late stage of the COVID-19 pandemic in China

Mirtazapine attenuates anxiety- and depression-like behaviors in rats during cocaine withdrawal

Fenfluramine acts as a positive modulator of sigma-1 receptors

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