The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear

Huang, Fang; Yang, Zehua; Li, C.-Q.

doi:10.1016/bs.vh.2016.09.003

Cited by 13 publications

(14 citation statements)

References 62 publications

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“…Melatonin regulates several mammalian biological processes such as circadian rhythm [483], sleep [484], reproduction [485], retinal physiology [478], glucose homeostasis [486], memory [487], blood pressure control [488], immune function [489] and free-radical scavenging [490]. Furthermore, other results suggest that melatonin has antinociceptive [491], antidepressant [492], antioxidant [493] and anxiolytic effects [494].…”

Section: Melatonin and Melatonin-receptorsmentioning

confidence: 99%

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Zavala-Tecuapetla

Cuéllar-Herrera

Luna-Munguía

2020

IJMS

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Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.

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Section: Melatonin and Melatonin-receptorsmentioning

confidence: 99%

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Zavala-Tecuapetla

Cuéllar-Herrera

Luna-Munguía

2020

IJMS

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“…Brain-derived neurotrophic factor (BDNF) and melatonin levels in the brain are reliable indicators of stressinduced cognitive deterioration [20,30]. The brain BDNF levels of IUS mice were significantly lower than those of control mice (Fig.…”

Section: Brain-derived Neurotrophic Factor and Melatonin Levels In Pementioning

confidence: 99%

“…IUS exposure was associated with increased stress hormone levels and proinflammatory cytokine secretion. IUS mice also showed hyperactivity, an anxiety-like behavior, and had lower biomarker levels of brain cognitive function than control mice [30,31]. The body weight of IUS mice decreased by 2-3 g after exposure to 24-h stress, but it recovered within 24 h.…”

mentioning

confidence: 99%

A Novel Animal Model Simulating the Beginning of Combat Exposure

Kim

Koo

et al. 2017

Neuroimmunomodulation

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Objective: Predator stress, social defeat stress, and fear conditioning animal models have been applied to investigate combat-related posttraumatic stress disorder (PTSD). However, no animal model psychopharmacological studies have investigated prevention of somatization of increased mental stress and fatigue at the beginning of combat exposure. This study utilized a novel animal model simulating the beginning of combat exposure that aided specification of a set of biomarkers. Methods: Psychological stress was induced by both inescapable electric foot shock and noise stimuli. Physical fatigue was induced by sleep deprivation and forced exercise in a rotating cage. A new device reflecting simultaneous psychological stress and physical fatigue was constructed. The protocol simulating combat exposure was set as 3 rounds of 24-h exposure in a 2-week period, which was specified as intermittent unpredictable stress (IUS). Results: Mice exposed to IUS(IUS mice) had significantly higher serum corticosterone levels (p < 0.05), excessive locomotive activity (p < 0.001), and anxiety-like behavior (p < 0.02) compared to control mice. IUS mice also had significantly higher IFN-γ (p < 0.001) and TNF-α (p < 0.05) levels in the supernatant of splenic T-cell culture compared to control mice. Brain-derived neurotropic factor levels were significantly decreased (p < 0.04) after IUS exposure. Conclusion: The proposed animal model of combat exposure reflected cognitive function impairment, behavior disturbance, and altered neuroimmune interactions without any apparent histopathological changes, and this animal model may be more applicable to protective research on war syndrome than combat-related PTSD after war because the hypothalamic-pituitary-adrenal axis has not been blunted.

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“… 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%

“… 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. 23 , 100 , 103 , 127 …”

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

confidence: 99%

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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The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear

Cited by 13 publications

References 62 publications

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

A Novel Animal Model Simulating the Beginning of Combat Exposure

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

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