Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus

Garcia, Lêda Soares Brandão; Comim, Clarissa M.; Valvassori, Samira S.; Réus, Gislaine Z.; Barbosa, Luciana Mendonça; Andreazza, Ana Cristina; Stertz, Laura; Fries, Gabriel R.; Gavioli, Elaine C.; Kapczinski, Flávio; Quevedo, Joao L De

doi:10.1016/j.pnpbp.2007.07.027

Cited by 406 publications

(266 citation statements)

References 37 publications

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“…In animal models of depression, ketamine has been shown to reverse despair behavior and anhedonia, supposedly via an effect on the hippocampus. Indeed, ketamine rapidly increases mTOR-dependent synaptogenesis in the hippocampus (Garcia et al, 2008) and increases hippocampal brainderived neurotrophic factor (BDNF) and mammalian target of rapamycin levels during the FST in rats (Tizabi et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

Belujon

Jakobowski

Dollish

et al. 2015

Neuropsychopharmacol

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Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats. Despair behavior using the modified forced swim test (FST) and dopamine (DA) activity in the ventral tegmental area using in vivo electrophysiological recordings were studied 18, 48 and 72 h after injection of amphetamine. The effects of inactivation of the basolateral amygdala (BLA) and ketamine administration on VTA DA neuron activity and passivity in the modified FST were examined. Eighteen hours following amphetamine withdrawal, there was a substantial decrease in the number of active DA neurons, as well as an increase in time spent immobile in the modified FST, which returned to baseline after 72 h. Inactivation of the BLA after acute amphetamine prevented the decrease in DA neuron tonic activity. Injection of ketamine also prevented the decrease in DA population activity but had no effect on immobility measured in the modified FST. The data support a model in which the negative affective state following acute amphetamine withdrawal is associated with a decrease in DA neuron population activity, driven by hyperactivity of the BLA. Although ketamine reversed the hypodopaminergic state following withdrawal, the failure to reduce immobility in the modified FST indicates that different processes underlying negative emotional state may exist between depression and drug withdrawal.

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Section: Discussionmentioning

confidence: 99%

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

Belujon

Jakobowski

Dollish

et al. 2015

Neuropsychopharmacol

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“…Additionally, ketamine, an NMDA receptor antagonist, has been shown in multiple anecdotal and two randomized trials to have efficacy in depression (Kudoh et al, 2002;Berman et al, 2000;Zarate et al, 2006). Importantly, ketamine and other NMDA receptor antagonists do have activity in some animal models predictive of antidepressant activity, such as the forced swim test (Garcia et al, 2007;Maj et al, 1992;Trullas and Skolnick, 1990). However, until clinical evidence for ketamine efficacy began to emerge, these studies did not lead a focus on NMDA receptors as a target for antidepressant medications.…”

Section: The Problem Of the Gap Between Traditional Academic Science mentioning

confidence: 99%

Opportunities and Challenges of Psychiatric Drug Discovery: Roles for Scientists in Academic, Industry, and Government Settings

Conn

Roth

2008

Neuropsychopharmacol

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Despite significant progress in understanding the biological systems and mechanisms involved in CNS disorders, use of this knowledge to realize practical gains in psychiatric care has been slow. To gain further insight into the reasons for failure and success in CNS drug discovery, preclinical predictors of success and failure for CNS drug discovery were evaluated for drugs developed for schizophrenia, depression, and anxiety. Specifically, we examined the success rate for drugs that had entered at least the later stages of preclinical research. Almost 500 compounds (140 antipsychotic; 211 antidepressant; 143 anxiolytic) were classified based on their molecular target(s) and evaluated based on preclinical validation, whether preclinical studies predicted clinical efficacy, and whether the compound displayed greater efficacy than 'conventional treatment' Results varied with indication but suggest that preclinical models have modest to good ability to predict overall clinical efficacy and adverse effect liability but are less able to predict efficacy greater than conventional treatment. In order to fully realize the potential therapeutic impact of recent basic science discoveries, it will be critical to increase attention on rigorous target validation at each step of the drug discovery process and focus efforts on developing new tools and clinical models that can be used for proof-of-concept studies in early clinical development. Also, increased attention should be focused on the development of early predictors of adverse effects of candidate compounds.

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“…Ketamine has been shown to have behavioural antidepressant-like effects in several other studies (60 min to weeks after the treatment) (Garcia et al, 2008;Dutta et al, 2015;Kavalali and Monteggia, 2015;Monteggia and Zarate, 2015). The recent clinical studies have focused on the rapid reduction of the suicidal ideation in patients with severe depression following a single ketamine administration.…”

Section: Discussionmentioning

confidence: 99%

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

Ardalan

Rafati

Nyengaard

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEAstroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes' morphology in a genetic animal model of depression. EXPERIMENTAL APPROACHS-Ketamine (15 mg·kg À1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test. KEY RESULTSFSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment. CONCLUSIONS AND IMPLICATIONSOur results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour. AbbreviationsBDNF, brain-derived neurotrophic factor; CA1.SR, CA1 stratum radiatum; EAAT, excitatory amino acid transporter; FRL, Flinders resistant line; FSL, Flinders sensitive line; GCL, granular cell layer of dentate gyrus; GFAP, glial fibrillary acid protein; MDG, molecular layer of dentate gyrus

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Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus

Cited by 406 publications

References 37 publications

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

Opportunities and Challenges of Psychiatric Drug Discovery: Roles for Scientists in Academic, Industry, and Government Settings

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

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