Gap Junction Blockers: An Overview of their Effects on Induced Seizures in Animal Models

Manjarrez-Marmolejo, Joaquín; Franco-Pérez, Javier

doi:10.2174/1570159x14666160603115942

Cited by 87 publications

(83 citation statements)

References 123 publications

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“…Consistent with this, other groups have noted that persistent epileptiform bursting leads to a reduced sensitivity of neurons to diazepam (Kapur and Macdonald, ; Dreier et al, ; Goodkin et al, ; Burman et al, ). Notably, previous work showed that gap‐junction blockers also affect the two models differently, giving mixed results appearing to enhance (Voss et al, ) activity in 0 Mg 2+ , but suppressing 4AP‐induced activity (Chang et al, ; Manjarrez‐Marmolejo and Franco‐Perez, ).…”

Section: Discussionmentioning

confidence: 98%

Divergent paths to seizure‐like events

et al. 2019

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Much debate exists about how the brain transitions into an epileptic seizure. One source of confusion is that there are likely to be critical differences between experimental seizure models. To address this, we have compared the evolving activity patterns in two widely used in vitro models of epileptic discharges. Brain slices from young adult mice were prepared in the same way and bathed either in 0 Mg2+ or 100 µmol/L 4AP artificial cerebrospinal fluid. We have found that while local field potential recordings of epileptiform discharges in the two models appear broadly similar, patch‐clamp analysis reveals an important difference in the relative degree of glutamatergic involvement. 4AP affects parvalbumin‐expressing interneurons more than other cortical populations, destabilizing their resting state and inducing spontaneous bursting behavior. Consequently, the most prominent pattern of transient discharge (“interictal event”) in this model is almost purely GABAergic, although the transition to seizure‐like events (SLEs) involves pyramidal recruitment. In contrast, interictal discharges in 0 Mg2+ are only maintained by a very large glutamatergic component that also involves transient discharges of the interneurons. Seizure‐like events in 0 Mg2+ have significantly higher power in the high gamma frequency band (60–120Hz) than these events do in 4AP, and are greatly delayed in onset by diazepam, unlike 4AP events. We, therefore, conclude that the 0 Mg2+ and 4AP models display fundamentally different levels of glutamatergic drive, demonstrating how ostensibly similar pathological discharges can arise from different sources. We contend that similar interpretative issues will also be relevant to clinical practice.

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Section: Discussionmentioning

confidence: 98%

Divergent paths to seizure‐like events

et al. 2019

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“…Notably, applying a CB1 receptor antagonist (rimonabant) to cannabis-dependent patients substituted with THC analogs did not precipitate a relevant CWS 63. This may be due to the low doses of rimonabant applied (20 and 40 mg) or the CWS-generating mechanisms that are at least partly independent upon CB1 receptors 49,50. Cannabis users with opioid dependence are less likely to experience CWS,64 which may indicate the contribution of the endogenous opioid system.…”

Section: Human Biological Backgroundmentioning

confidence: 93%

The cannabis withdrawal syndrome: current insights

Bonnet¹,

Preuss

2017

SAR

176

127

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The cannabis withdrawal syndrome (CWS) is a criterion of cannabis use disorders (CUDs) (Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition) and cannabis dependence (International Classification of Diseases [ICD]-10). Several lines of evidence from animal and human studies indicate that cessation from long-term and regular cannabis use precipitates a specific withdrawal syndrome with mainly mood and behavioral symptoms of light to moderate intensity, which can usually be treated in an outpatient setting. Regular cannabis intake is related to a desensitization and downregulation of human brain cannabinoid 1 (CB1) receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning within 4 weeks of abstinence, which could constitute a neurobiological time frame for the duration of CWS, not taking into account cellular and synaptic long-term neuroplasticity elicited by long-term cannabis use before cessation, for example, being possibly responsible for cannabis craving. The CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Therefore, naturalistic severity of CWS highly varies. Women reported a stronger CWS than men including physical symptoms, such as nausea and stomach pain. Comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably qualified detox) and post-acute rehabilitation. There are promising results with gabapentin and delta-9-tetrahydrocannabinol analogs in the treatment of CWS. Mirtazapine can be beneficial to treat CWS insomnia. According to small studies, venlafaxine can worsen the CWS, whereas other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect. Certainly, further research is required with respect to the impact of the CWS treatment setting on long-term CUD prognosis and with respect to psychopharmacological or behavioral approaches, such as aerobic exercise therapy or psychoeducation, in the treatment of CWS. The up-to-date ICD-11 Beta Draft is recommended to be expanded by physical CWS symptoms, the specification of CWS intensity and duration as well as gender effects.

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“…Consistent with this, other groups have noted that persistent epileptiform bursting leads to a reduced sensitivity of neurons to diazepam 35–38 . Notably, previous work showed that gap-junction blockers also affect the two models differently, giving mixed results appearing to enhance 39 activity in 0 Mg 2+ , but suppressing 4AP induced activity 40,41 .…”

Section: Discussionmentioning

confidence: 98%

Divergent paths to seizure-like events

Codadu

Graham

Burman

et al. 2019

Preprint

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1 Aim: Much debate exists about how the brain transitions into an epileptic seizure. One 2 source of confusion is that there are likely to be critical differences between experimental 3 seizure models. To address this, we compared the evolving activity patterns in two, widely 4 used, in vitro models of epileptic discharges. 5Methods: We compared brain slices, prepared in the same way from young adult mice, 6 that were bathed either in 0 Mg 2+ , or 100µM 4AP, artificial cerebrospinal fluid. 7Results: We find that while local field potential recordings of epileptiform discharges in 8 the two models appear broadly similar, patch-clamp analysis reveals an important 9 difference in the relative degree of glutamatergic involvement. 4AP affects parvalbumin-10 expressing interneurons more than other cortical populations, destabilizing their resting 11 state and inducing spontaneous bursting behavior. Consequently, the most prominent 12 pattern of transient discharge ("interictal event") in this model is almost purely 13 GABAergic, although the transition to seizure-like events (SLEs) involves pyramidal 14 recruitment. In contrast, interictal discharges in 0 Mg 2+ are only maintained by a very 15 large glutamatergic component that also involves transient discharges of the interneurons. 16 Seizure-like events in 0 Mg 2+ have significantly higher power in the high gamma 17 frequency band (60-120Hz) than these events do in 4AP, and are greatly delayed in onset 18 by diazepam, unlike 4AP events. 19 Conclusions: The 0 Mg 2+ and 4AP models display fundamentally different levels of 20 glutamatergic drive, demonstrating how ostensibly similar pathological discharges can 21 arise from different sources. We contend that similar interpretative issues will also be 22 relevant to clinical practice. 23 24 Slice preparation: Male and female Emx1-Cre (B6.129S2-Emx1tm1(cre)Krj/J; Jackson 11 Laboratory stock number 5628), PV-Cre (B6;129P2-Pvalb/J; Jackson 12 Laboratory stock number 8069), and SOM-Cre (B6N.Cg.Ssttm2.1(cre)Zjh/J; Jackson 13 Laboratory stock number 18973) mice and C57/B6 mice (ages 3 -12 weeks) were used in this 14 study. Transgenic mice were back-crossed with the C57/B6 line maintained at Newcastle 15 University, and subsequently maintained on this C57/B6 background (Jackson Laboratory stock 16 number 000664). Mice were housed in individually ventilated cages in a 12 hours light, 12 17 hours dark lighting regime. Animals received food and water ad libitum. Mice were sacrificed 18 by cervical dislocation, brains removed and stored in cold cutting solution (in mM): 3 MgCl 2 ; 19126 NaCl; 26 NaHCO 3 ; 3.5 KCl; 1.26 NaH 2 PO 4 ; 10 glucose. For local field potential (LFP) 20 recordings, 400µm horizontal sections were made, using a Leica VT1200 vibratome (Nussloch, 21 Germany). Slices were then transferred to an interface holding chamber and incubated for 1-2 22 hours at room temperature in artificial CSF (ACSF) containing (in mM): 2 CaCl 2 ; 1 MgCl 2 ; 126 23 NaCl; 26 NaHCO 3 ; 3.5 KCl; 1.26 NaH 2 PO 4 ; 10 glu...

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Gap Junction Blockers: An Overview of their Effects on Induced Seizures in Animal Models

Cited by 87 publications

References 123 publications

Divergent paths to seizure‐like events

Divergent paths to seizure‐like events

The cannabis withdrawal syndrome: current insights

Divergent paths to seizure-like events

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