Ketamine prevents seizures and reverses changes in muscarinic receptor induced by bicuculline in rats

Schneider, Patricia G.; Arnaiz, Georgina Rodrı́guez de Lores

doi:10.1016/j.neuint.2012.12.013

Cited by 11 publications

(6 citation statements)

References 33 publications

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“…Notably, this drug effect occurred despite the impairment of inhibitory synapses that is evident in untreated γ2 +/− mice. An enduring potentiation of synaptic inhibition is consistent with the known seizure suppressing effects of ketamine (57–59). …”

Section: Discussionsupporting

confidence: 80%

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Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment

Ren

Pribiag

Jefferson

et al. 2016

Biological Psychiatry

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Background Major depressive disorder (MDD) is increasingly recognized to involve functional deficits in both GABAergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes we made use of GABAA receptor γ2 subunit heterozygous (γ2+/−) mice, which we previously characterized as a model animal with construct, face and predictive validity for MDD. Methods To assess possible consequences of GABAergic deficits on glutamatergic transmission we quantitated the cell surface expression of NMDA- and AMPA-type glutamate receptors and the function of synapses in the hippocampus and medial prefrontal cortex of γ2+/− mice. In addition, we analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in γ2+/− vs. wild-type mice. Results Modest defects in GABAergic synaptic transmission of γ2+/− mice resulted in a strikingly prominent homeostatic-like reduction in the cell surface expression of NMDA- and AMPA-type glutamate receptors, along with prominent functional impairment of glutamatergic synapses in the hippocampus and medial prefrontal cortex (mPFC). A single subanesthetic dose of ketamine lastingly normalized the glutamate receptor expression and synaptic function of γ2+/− mice to wild-type levels, along with antidepressant-like behavioral consequences selectively in γ2+/− mice. GABAergic synapses of γ2+/− mice were potentiated by ketamine in parallel but only in mPFC. Conclusions Depressive-like brain states that are caused by GABAergic deficits involve a homeostatic-like reduction of glutamatergic transmission that is reversible by an acute, subanesthetic dose of ketamine, along with regionally selective potentiation of GABAergic synapses. The data merge the GABAergic and glutamatergic deficit hypothesis of MDD.

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Section: Discussionsupporting

confidence: 80%

“…Ketamine has potent seizure-suppressing effects in animal models of epilepsy and in patients (57–59). We therefore wondered whether ketamine-induced potentiation of glutamatergic transmission was accompanied by an increase in GABAergic inhibition.…”

Section: Resultsmentioning

confidence: 99%

Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment

Ren

Pribiag

Jefferson

et al. 2016

Biological Psychiatry

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“…Previous studies have shown that this dose of bicuculline is effective at inducing cognitive and neurophysiological alterations, whereas lower doses (12.5 ng) are less effective (Enomoto et al, 2011;Paine et al, 2011). Moreover, this dose is orders of magnitudes lower than those used to induce epileptiform activity (Schneider and de Lores Arnaiz, 2013). Infusion was conducted over 75 s, with injectors left in place for 60 s to allow for diffusion from cannula tips.…”

Section: Microinfusionmentioning

confidence: 99%

Prefrontal Cortical GABA Transmission Modulates Discrimination and Latent Inhibition of Conditioned Fear: Relevance for Schizophrenia

Piantadosi

Floresco

2014

Neuropsychopharmacol

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Inhibitory gamma-aminobutyric acid (GABA) transmission within the prefrontal cortex (PFC) regulates numerous functions, and perturbations in GABAergic transmission within this region have been proposed to contribute to some of the cognitive and behavioral abnormalities associated with disorders such as schizophrenia. These abnormalities include deficits in emotional regulation and aberrant attributions of affective salience. Yet, how PFC GABA regulates these types of emotional processes are unclear. To address this issue, we investigated the contribution of PFC GABA transmission to different aspects of Pavlovian emotional learning in rats using translational discriminative fear conditioning and latent inhibition (LI) assays. Reducing prelimbic PFC GABAA transmission via infusions of the antagonist bicuculline before the acquisition or expression of fear conditioning eliminated the ability to discriminate between an aversive conditioned stimulus (CS+) paired with footshock vs a neutral CS-, resembling similar deficits observed in schizophrenic patients. In a separate experiment, blockade of PFC GABAA receptors before CS preexposure (PE) and conditioning did not affect subsequent expression of LI, but did enhance fear in rats that were not preexposed to the CS. In contrast, PFC GABA-blockade before a fear expression test disrupted the recall of learned irrelevance and abolished LI. These data suggest that normal PFC GABA transmission is critical for regulating and mitigating multiple aspects of aversive learning, including discrimination between fear vs safety signals and recall of information about the irrelevance of stimuli. Furthermore, they suggest that similar deficits in emotional regulation observed in schizophrenia may be driven in part by deficient PFC GABA activity.

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“…5 As it is a very potent and selective muscarinic ligand with higher affinity for the M2 subtype of muscarinic receptors when administered in vivo, 6 nowadays it is used especially to identify muscarinic receptors in various studies. A radioactive labeled BZ compound was used, for example, as a model agent for the development of a total serum anticholinergic activity assay based on cultured Chinese hamster ovary cells, 7 to investigate the ability of selected drugs to affect the binding characteristics of muscarinic receptors [8][9][10] or to detect changes in the expression of muscarinic receptors during inflammation 11 or organophosphate poisoning. 12 Due to its anticholinergic activity, BZ agent can also be used for the pharmacologic induction of cognitive impairment in rats in order to evaluate the pro-cognitive effects of newly developed potential drugs for the therapy of Alzheimer's disease and other neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

“…As it is a very potent and selective muscarinic ligand with higher affinity for the M2 subtype of muscarinic receptors when administered in vivo, nowadays it is used especially to identify muscarinic receptors in various studies. A radioactive labeled BZ compound was used, for example, as a model agent for the development of a total serum anticholinergic activity assay based on cultured Chinese hamster ovary cells, to investigate the ability of selected drugs to affect the binding characteristics of muscarinic receptors or to detect changes in the expression of muscarinic receptors during inflammation or organophosphate poisoning …”

Section: Introductionmentioning

confidence: 99%

Simple validated method of LC–MS/MS determination of BZ agent in rat plasma samples

Herman

Dlabková

Cechova

et al. 2020

Drug Testing and Analysis

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Agent BZ (3‐quinuclidinyl benzilate) is a centrally acting synthetic anticholinergic agent, considered as a potential military incapacitating chemical warfare agent. Despite its significance as a model compound in pharmacological research and its potential misuse in chemical attacks, few modern analytical methods for BZ determination in biological samples have been published. The goal of the present work is to develop and validate a sensitive and rapid LC–MS/MS method for the determination of agent BZ in rat plasma. The sample preparation was based on solid‐phase extraction on C‐18 cartridges. The reversed‐phase HPLC coupled with the mass spectrometer with electrospray ionization in the positive ion‐selective reaction monitoring mode was employed in the BZ analysis. Atropine was used as an internal standard. The presented method is selective, accurate, precise, and linear (r2 = 0.9947) in a concentration range from 0.5 ng/mL to 1 000 ng/mL and sensitive enough (limit of detection 0.2 ng/mL; limit of quantification 0.5 ng/mL) to determine the BZ plasma levels in rats exposed to 2 mg/kg and 10 mg/kg of BZ. The highest level of BZ in plasma was observed 5 minutes after intramuscular administration (154.6 ± 22.3 ng/mL in rats exposed to 2 mg/kg of BZ and 1024 ± 269 ng/mL in rats exposed to 10 mg/kg). After 48 h, no BZ was observed at detectable levels. This new method allows the detection and quantification of BZ in biological samples after exposure of an observed organism and it will be further optimized for other tissues to observe the distribution of BZ in organs.

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Ketamine prevents seizures and reverses changes in muscarinic receptor induced by bicuculline in rats

Cited by 11 publications

References 33 publications

Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment

Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment

Prefrontal Cortical GABA Transmission Modulates Discrimination and Latent Inhibition of Conditioned Fear: Relevance for Schizophrenia

Simple validated method of LC–MS/MS determination of BZ agent in rat plasma samples

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