Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake

Brocco, Mauricette; Dekeyne, Anne; Veiga, Sylvie; Girardon, Sylvie; Millan, Mark J.

doi:10.1016/s0091-3057(01)00701-8

Cited by 105 publications

(75 citation statements)

References 81 publications

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“…S1A): there was no Stress effect on % time freezing (p=0.85); there was a main effect of Drug (F 1,48 =5.71, p<0.03) with ESC mice displaying lower freezing than VEH mice. Reduced freezing by ESC mice cooccurred with higher locomotor activity during non-freezing periods (data not shown), consistent with the reported effects of acute SSRI on mouse activity (Brocco et al, 2002). In CON but not in CSD mice, ESC also induced hyper-locomotion on days 17 and 18 (data not shown).…”

Section: Csd Increased Fear Behaviour and Escitalopram Reversed This supporting

confidence: 86%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

118

125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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Section: Csd Increased Fear Behaviour and Escitalopram Reversed This supporting

confidence: 86%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

118

125

View full text Add to dashboard Cite

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“…However, a decrease in the time spent in the central area in the open field test was also reported elsewhere, suggesting an anxiogenic effect [63]. Duloxetine also increases exploratory behavior in a novel environment [65] and it provokes a dose-dependent reduction in stress-induced ultrasonic vocalization [66], indicative of an anxiolytic-like effect.…”

Section: Antidepressant Activitysupporting

confidence: 72%

“…Acute; 2 --40 mg/kg s.c. "Locomotor activity [65] 5-HTTP: 5-hydroxytryptophan; 8-OHDPAT: (8-hydroxyl-2-(di-n-propylamino)tetralin; EEG: Electroencephalogram; i. Anxiolytic effects of chronic duloxetine have been reported, as evident through an increase in the time spent in the open area in the zero maze test [35,64]. However, a decrease in the time spent in the central area in the open field test was also reported elsewhere, suggesting an anxiogenic effect [63].…”

Section: Antidepressant Activitymentioning

confidence: 99%

Preclinical discovery of duloxetine for the treatment of depression

Torres-Sánchez

Pérez-Caballero

Micó

et al. 2012

Expert Opinion on Drug Discovery

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“…We used an SSRI rather than benzodiazepines to demonstrate this neurobiological anxiolytic drug action since, unlike benzodiazepines, SSRIs have not been shown to affect basal hippocampal ACh levels. In Experiment 3, fluoxetine was administered acutely, given that chronic administration of SSRIs is not required to show an anxiolytic effect in animals (Brocco et al, 2002;Muraki, 2001). This may be due to the fact that the animals tested do not suffer from unusually low serotonin levels as those purportedly found in the clinical population.…”

Section: Resultsmentioning

confidence: 99%

Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

Degroot

Nomikos

2004

Neuropsychopharmacol

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Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac s ) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.

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Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake

Cited by 105 publications

References 81 publications

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Preclinical discovery of duloxetine for the treatment of depression

Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

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