Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

Amat, José; Dolzani, Samuel D.; Tilden, Scott; Christianson, John P.; Kubala, Kenneth H.; Bartholomay, Kristi L.; Sperr, Katherine; Ciancio, Nicholas; Watkins, Linda R.; Maier, Steven F.

doi:10.1523/jneurosci.3114-15.2016

Cited by 70 publications

(70 citation statements)

References 36 publications

(27 reference statements)

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“…These results are consistent with dysregulated fear and HPA axis reactivity in PTSD. A wealth of studies indicate that the PFC is critical for detection of stressor controllability [80••, 82–85] consistent with observations that impaired PFC function may be an important mediator of PTSD symptoms.…”

Section: Animal Models Of Ptsdsupporting

confidence: 65%

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Girgenti

Hare

Ghosal

et al. 2017

Curr Psychiatry Rep

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Purpose of Review Posttraumatic stress disorder (PTSD) is characterized by hyperarousal and recurrent stressful memories after an emotionally traumatic event. Extensive research has been conducted to identify the neurobiological determinants that underlie the pathophysiology of PTSD. In this review, we examine evidence regarding the molecular and cellular pathophysiology of PTSD focusing on two primary brain regions: the vmPFC and the amygdala. Recent Findings This discussion includes a review of the molecular alterations related to PTSD, focusing mainly on changes to glucocorticoid receptor signaling. We also examine postmortem gene expression studies that have been conducted to date and the molecular changes that have been observed in peripheral blood studies of PTSD patients. Causal, mechanistic evidence is difficult to obtain in human studies, so we also review preclinical models of PTSD. Summary Integration of peripheral blood and postmortem studies with preclinical models of PTSD has begun to reveal the molecular changes occurring in patients with PTSD. These findings indicate that the pathophysiology of PTSD includes disruption of glucocorticoid signaling and inflammatory systems and occurs at the level of altered gene expression. We will assess the impact of these findings on the future of PTSD molecular research.

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Section: Animal Models Of Ptsdsupporting

confidence: 65%

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Girgenti

Hare

Ghosal

et al. 2017

Curr Psychiatry Rep

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“…In vitro experiments have shown that ketamine is a 5-HT receptor agonist, which may inhibit complex G protein-coupled receptors, such as adrenaline and muscarinic and opioid receptors (1,24). Some studies (25,26) used ketamine to anesthetize rats and to detect DA, NE, 5-HT, and 5-HIAA in brain, finding that when rats were deeply anesthetized, the 5-HT content was increased but 5-HIAA showed an opposite trend. The contents of NE and DA were significantly increased during ketamine anesthesia and the recovery process.…”

Section: Discussionmentioning

confidence: 99%

Effects of ketamine on monoamine neurotransmittersand GABA in embryonic neurocytes from fetal rat

Li¹,

Liu²,

Li³

et al. 2017

Turk J Vet Anim Sci

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IntroductionKetamine can selectively inhibit specific parts of the central nervous system, especially at the level of the communication channel and the thalamocortical network of the brain. Ketamine is characterized by its peculiar ability to separate pain and consciousness, called "separation anesthesia" (1).Classical ion receptor channels are mainly activated by norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and γ-aminobutyric acid (GABA). These neurotransmitters not only regulate neuronal excitability but also have a strong impact on the development of the brain. For example, DA is retained in vesicles at the nerve endings. When a nerve impulse arrives, the vesicle is emptied and DA is released. DA receptors on the cell membrane can bind to the neurotransmitter, thus transmitting the information. However, neurotransmitters can interact among them. 5-HT antagonist can be enhanced by amphetamine-induced locomotor activity (2) and can inhibit dystonia and catalepsy caused by diazepam (3).However, to this day, little is known about the effects of ketamine on the levels of GABA, DA, NE, 5-HT, and 5-HIAA in neurocyte cell cultures from fetal rats. We thus decided to investigate how different concentrations of ketamine may affect these neurotransmitters at the neurocyte level. Materials and methods AnimalsMale and female Wistar rats, 3 months old and weighing 200 ± 20 g, were purchased from the Animal Experimental Center of the Second Affiliated Hospital of Harbin Medical University (Harbin, China). Prior to the experiment, rats were quarantined for 2 weeks at the Northeast Agricultural University (Harbin, China). A total of 104 rats were randomly divided into low-dose groups (L group, n = 32, 4 subgroups), middle-dose groups (M group, n = 48, 6 subgroups), and high-dose groups (H group, n = 24, 3 subgroups), with 8 rats in each subgroup. Intraperitoneal injections of ketamine (Shenyang Veterinary Drug Factory, 20110908) were as follows: L group with 10, 20, 30, and 40 mg/kg; M group with 50, 60, 70, 80, 90, and 100 mg/kg; and H group with 150, 200, and 300 mg/kg. Cerebrospinal fluid was sampled from the cisterna magna as described previously (4). Cerebrospinal fluid was extracted from the foramen magnum to measure the ketamine concentration

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“…This dose was chosen based on previous studies in rodents (Lopez-Gil et al, 2007;Fukumoto et al, 2016). Second, the GABAA-R agonist, muscimol (8 nmol) was injected into the mPFC (Sigma-Aldrich, Saint-Quentin Fallavier, France), according to Amat et al, (2016). Third, the inhibitor of GLUT-1 glutamatergic transporter, dihyrokainic acid (DHK, Tocris Bioscience, Lille, France) was dissolved in the aCSF and perfused at 5 mM for 2.5 hours according to Gasull-Camos et al, (2017).…”

Section: Drugs and Treatmentsmentioning

confidence: 99%

“…Animal models of anxiety/depression contribute robustly to study ketamine's mechanism of action (Pham et al, 2019). 80% of medial prefrontal cortex (mPFC) neurons are excitatory and the mPFC contains a dense network of glutamate releasing nerve terminals (Gasull-Camos et al, 2017) that project to the dorsal raphe nucleus (DRN) (Amat et al, 2016). In addition, NMDA-R, the main target of ketamine, is widely expressed in this brain region (Murray et al, 2000;Kamiyama et al, 2011;Sanz-Clemente et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Here we assessed the behavioral and neurochemical effects of ketamine by coupling microdialysis in the mPFC and FST in BALBc/J mice. In a pharmacological approach, we used a pre-treatment with AMPA-R antagonist (intra-DRN NBQX: Nishitani et al, 2014), GABAA-R agonist (intra-mPFC muscimol: Amat et al, 2016) administered thirty minutes before ketamine to study the specific role of excitatory and inhibitory neurotransmission in the mPFC-DRN circuit. Extracellular levels of glutamate, GABA and 5-HT (Gluext, GABAext, and 5-HText, respectively) were examined in the mPFC.…”

Section: Introductionmentioning

confidence: 99%

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Cortical and raphe GABA_A, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

Pham

Lavialle-Defaix

Nguyen

et al. 2020

Preprint

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ABSTRACTAt sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABAA-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HText and Gluext. Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HText. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HText, Gluext and GABAext. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABAA-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.

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Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

Cited by 70 publications

References 36 publications

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Effects of ketamine on monoamine neurotransmittersand GABA in embryonic neurocytes from fetal rat

Cortical and raphe GABA_A, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

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Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

Cited by 70 publications

References 36 publications

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Effects of ketamine on monoamine neurotransmittersand GABA in embryonic neurocytes from fetal rat

Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

Contact Info

Product

Resources

About

Cortical and raphe GABA_A, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine