Fear Erasure in Mice Requires Synergy Between Antidepressant Drugs and Extinction Training

Karpova, Nina N.; Pickenhagen, Anouchka; Lindholm, Jesse; Tiraboschi, Ettore; Kulesskaya, Natalia; Agustsdottir, Arna; Antila, Hanna; Popova, Dina; Akamine, Yumiko; Sullivan, Regina M.; Hen, René; Drew, Liam; Ċastrén, Eero

doi:10.1126/science.1214592

Cited by 354 publications

(448 citation statements)

References 41 publications

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“…Similarly, alterations in the serotonergic circuitry is seen in individuals with AN, a disorder characterized by CR (Kaye et al, , 2009). Chronic treatment with fluoxetine enhances extinction learning and retention in mice, and these effects have been proposed to explain its anxiolytic properties (Karpova et al, 2011). In our studies, CR displayed SSRI-like effects on extinction learning and retention that were absent from mice lacking SERT.…”

Section: Discussionsupporting

confidence: 55%

“…SSRIs are anxiolytic drugs that improve fear extinction retention (Karpova et al, 2011). Given that fluoxetine and CR have similar effects on the expression of SERT mRNA species, and that the effects of CR on fear extinction appear to act through SERT, we hypothesized that fluoxetine would increase extinction retention in AL-fed mice, but not in CR mice.…”

Section: Fluoxetine Enhances Fear Extinction Retention In Al Fed Micementioning

confidence: 99%

“…Reduced expression of SERT is seen in humans with anxiety disorders (Maron et al, 2004;Murrough et al, 2011;Reimold et al, 2007), and a polymorphism affecting SERT expression in humans has been associated with fear extinction retention, and risk for panic disorder (Gyawali et al, 2010;Hartley et al, 2012). Moreover, the SERTtargeting selective serotonin reuptake inhibitors (SSRI's) enhance fear extinction retention (Karpova et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Caloric Restriction Enhances Fear Extinction Learning in Mice

Riddle

McKenna

Yoon

et al. 2013

Neuropsychopharmacol

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Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety.

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Section: Discussionsupporting

confidence: 55%

Section: Fluoxetine Enhances Fear Extinction Retention In Al Fed Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Caloric Restriction Enhances Fear Extinction Learning in Mice

Riddle

McKenna

Yoon

et al. 2013

Neuropsychopharmacol

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Section: From Stressful Events To Depression: Clues From Maladaptivementioning

confidence: 94%

“…Fluoxetine treatment acts synergistically with extinction to erase conditioned fear in mice, possibly by enhancing LTP and brain-derived neurotrophic factor (BDNF) expression in the lateral amygdala. Indeed, this effect was not observed in BDNF -/+ mice, while the effects of fluoxetine were mimicked by BDNF overexpression [69] .Antidepressants can also restore impaired memory performance in depression models by rescuing impaired LTP induction and by maintaining dendritic morphological complexity and hippocampal neurogenesis.Changes in neural plasticity caused by chronic stress may alter cognition and behavior in humans, and this may lead to depressive symptoms. In depression, the encoding and retrieval of negative memories may be facilitated, and so come to dominate cognition and exert a prominent infl uence on behavior.…”

mentioning

confidence: 97%

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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Neuronal Network Plasticity and Recovery From Depression

2013

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The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: The effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.

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Fear Erasure in Mice Requires Synergy Between Antidepressant Drugs and Extinction Training

Cited by 354 publications

References 41 publications

Caloric Restriction Enhances Fear Extinction Learning in Mice

Caloric Restriction Enhances Fear Extinction Learning in Mice

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

Neuronal Network Plasticity and Recovery From Depression

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