Investigation of the anticonvulsive effect of acute immobilization stress in anxious Balb/cByJ mice using GABAA-related mechanistic probes

Verleye, Marc; Heulard, Isabelle; Gillardin, Jean-Marie

doi:10.1007/s00213-007-1066-7

Cited by 13 publications

(8 citation statements)

References 75 publications

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“…Clonazepam was diluted in saline (0.9% NaCL) and an appropriate vehicle control solution was administered. The dose of clonazepam (50μg/kg) was chosen based on literature in a model of restraint stress (Verleye, et al, 2008). A pilot study was conducted with HCC in order to obtain the same dose-response behavioral and spleen weight data obtained with lorazepam (data not shown).…”

Section: Methodsmentioning

confidence: 99%

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GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

Ramírez

Niraula

Sheridan

2016

Brain, Behavior, and Immunity

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Objective Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b+ /Ly6Chi) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: 1) prevent stress-induced peripheral and central inflammatory responses, and 2) block anxiety and social avoidance behavior in mice subjected to RSD. Methods C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9%NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Results Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b+/CD45high) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. Conclusion These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.

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Section: Methodsmentioning

confidence: 99%

“…Lorazepam and clonazepam are BDZs that act as positive allosteric modulators of GABA action with similar pharmacological mechanisms and share anxiolytic properties (Verleye et al, 2008; Saari et al, 2011). These two drugs have been used extensively to distinguish between the CBBS and the TSPO (Casellas, 2002).…”

Section: Introductionmentioning

confidence: 99%

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

Ramírez

Niraula

Sheridan

2016

Brain, Behavior, and Immunity

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“…Although the affinity of EFX for GABAARs was twice higher than the one for TSPO (Ki of 6.1 µM vs Ki of 12.7 µM), the predominance of one of the effect over the other, i.e. direct GABAARs binding or through TSPO activation, in mediating its anxiolytic effect, is still debated [25,28,29].…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we first compared EFX and BZP in anxiolysis, sedation and locomotor impairment behavioral tests in acute conditions, in mice. The pharmacological effects of both EFX and BZP already appear after a single administration [8,9,29,30]. Here, we determined the anxiolytic doses of EFX and their possible influences on motor performance and arousal.…”

Section: Introductionmentioning

confidence: 99%

Involvement of the GABAA receptor α subunit in the mode of action of etifoxine

Mattei

Taly

Soualah

et al. 2019

Pharmacological Research

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Etifoxine (EFX) is a non-benzodiazepine psychoactive drug which exhibits anxiolytic effects through a dual mechanism, by directly binding to GABAA receptors (GABAARs) and to the mitochondrial 18-kDa translocator protein, resulting in the potentiation of the GABAergic function. The b subunit subtype plays a key role in the EFX-GABAAR interaction, however this does not explain the anxiolytic effects of this drug. Here, we combined behavioral and electrophysiological experiments to challenge the role of the GABAAR a subunit in the EFX mode of action. After single administrations of anxiolytic doses (25-50 mg/kg, intraperitoneal), EFX did not induce any neurological nor locomotor impairments, unlike the benzodiazepine bromazepam (0.5-1 mg/kg, intraperitoneal). We established the EFX pharmacological profile on heteropentameric GABAARs constructed with α1 to α6 subunit expressed in Xenopus oocyte. Unlike what is known for benzodiazepines, neither the γ nor δ subunits influenced EFX-mediated potentiation of GABA-evoked currents. EFX acted first as a partial agonist on α2b3γ2S, α3b3γ2S, α6b3γ2S and α6b3d GABAARs, but not on α1b3γ2S, α4b3γ2S, α4b3d nor α5b3γ2S GABAARs. Moreover, EFX exhibited much higher positive allosteric modulation towards α2b3γ2S, α3b3γ2S and α6b3γ2S than for α1b3γ2S, α4b3γ2S and α5b3γ2S GABAARs. At 20 µM, corresponding to brain concentration at anxiolytic doses, EFX increased GABA potency to the highest extent for α3b3γ2S GABAARs. We built a docking model of EFX on α3β3γ2S GABAARs, which is consistent with a binding site located between α and β subunits in the extracellular domain. In conclusion, EFX preferentially potentiates α2b3γ2S and α3b3γ2S GABAARs, which might support its advantageous anxiolytic/sedative balance.

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“…Rodent seizure models have revealed an important role for stress in promoting epilepsy. Several studies show both the proconvulsive (Joels, 2009; Sadaghiani and Saboory, 2010; Turner et al, 2007) as well as the anticonvulsive (Heshmatian et al, 2010; Verleye et al, 2008) effects of various type of stresses. Different stresses have different impacts on brain function and neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

Prenatal exposure to restraint or predator stresses attenuates field excitatory postsynaptic potentials in infant rats

Saboory

Ahmadzadeh

Roshan‐Milani

2011

Intl J of Devlp Neuroscience

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Exposure to stress is known to change synaptic plasticity and results in long-term depression; further, this stress precipitates seizures. In the study described here, the prenatal restraint and predator stress models were used to test the hypothesis that indirect prenatal stresses influence hippocampal synaptic potentiation and may affect seizures susceptibility in infant rats. Pregnant female Wistar rats were divided into 3 groups: control, restraint-stressed, and predator-stressed groups. Both stressed groups were exposed to the stressor on gestation days 15, 16, and 17. The restraint stress involved 1-h sessions twice daily in a Plexiglas tube and the predator stress involved 2-h sessions once daily in a cage placed within the visual range of a caged cat. Blood corticosterone (COS) levels were measured in different time points. Hippocampal slices were prepared and field excitatory postsynaptic potentials (fEPSP) were studied on postnatal day 15. Pilocarpine was administered on postnatal day 25 and mortality rates were measured after 2 and 24h. Restraint and predator stresses resulted in significantly elevated COS blood levels in dams and pups. Both the amplitude and slope of fEPSP in the CA1 area decreased significantly in the stressed groups as compared to the control. Prenatal restraint and predator stresses significantly increased the fatal effect of pilocarpine at 24h after injection. Exposure to prenatal stresses and COS blood levels elevation reduce hippocampal synaptic potentiation and increase mortality rate of seizure in infant rats and may affect on later seizure susceptibility and prognosis.

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Investigation of the anticonvulsive effect of acute immobilization stress in anxious Balb/cByJ mice using GABAA-related mechanistic probes

Cited by 13 publications

References 75 publications

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

Involvement of the GABAA receptor α subunit in the mode of action of etifoxine

Prenatal exposure to restraint or predator stresses attenuates field excitatory postsynaptic potentials in infant rats

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