Binding of3H-DMCM to benzodiazepine receptors; chloride dependent allosteric regulation mechanisms

Honoré, Tage; Nielsen, Mogens; Bræstrup, Claus

doi:10.1007/bf01249127

Cited by 11 publications

(6 citation statements)

References 30 publications

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“…The beta-carboline, DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate), is a potent and efficacious negative allosteric modulator of benzodiazepine-sensitive GABA A receptors (Braestrup et al, 1983, 1982; Honoré et al, 1983). DMCM reduces chloride flux through the GABA A receptor by decreasing the frequency of channel openings (Jensen and Lambert, 1983; Puia et al, 1991; Vicini et al, 1987, 1986); this decrease in inhibitory efficacy results in hyperexcitability.…”

Section: Introductionmentioning

confidence: 99%

Ontogenic profile of seizures evoked by the beta-carboline DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in rats

Kulick

Gutherz

Kondratyev

et al. 2014

European Journal of Pharmacology

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The beta-carboline, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), is a potent chemoconvulsant. While it has been utilized in adult rodents, it has not been previously examined for effects across postnatal development. DMCM is a negative allosteric modulator of benzodiazepine-sensitive GABAA receptors, receptor subtypes that are particularly enriched in limbic brain regions. This raises the possibility that DMCM may be particularly effective at evoking forebrain seizures, which is a challenge in neonatal animals due to the relative immaturity of the forebrain seizure network. The ability to selectively evoke forebrain seizures is desirable when screening for drugs to use in temporal lobe epilepsy, which is characterized by seizures within the forebrain (limbic) network. To determine the profile of DMCM action across development, we examined the dose-dependent ability of DMCM to induce seizures in rats at P7, P10, P13, P14, P21 and in adulthood. We found that the highest sensitivity to DMCM occurred in P10, P13, and P14 rats. The lowest sensitivity occurred in P21 rats. Neonatal (P7) and adult (P60+) rats displayed moderate sensitivity. With moderate (0.2–0.4mg/kg) doses of DMCM, we were able to reliably evoke limbic motor seizures without tonic-clonic components in animals as young as P7. These data support the utility of DMCM in assessing seizure threshold during development and raise the possibility for future exploration of DMCM as an agent to screen anticonvulsant drugs during the postnatal period.

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Section: Introductionmentioning

confidence: 99%

Ontogenic profile of seizures evoked by the beta-carboline DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in rats

Kulick

Gutherz

Kondratyev

et al. 2014

European Journal of Pharmacology

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“…This effect appeared restricted to agonists, because chloride did not alter the binding of a BzR antagonist (Ro 15-1788) or an inverse agonist (3-carboethoxy-0-carboline) (Mohler and Richards, 198 1 ;Williams et al, 1981). However, Honor6 et al (1983) reported that permeant anions augmented the binding of the convulsant ,f3-carboline [3H]DMCM to BzRs. The present studies comparing the effects of anions on ['HIDMCM and ['HIFNZ binding to BzRs were prompted by the recent observation that a brief ambient-temperature swim evoked a marked increase in the potency and efficacy of chloride to stimulate ['HIFNZ binding to well-washed cerebral cortical membranes (Havoundjian et al, 1986b;Trullas et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…The effect of chloride (10-500 mM) on [3H]DMCM and [3H]FNZ binding to cerebral cortical membranes is illustrated in Fig. 1 Honor6 et al, 1983), the increase in [3H]FNZ binding was no longer apparent (Fig. 1B and Costa et al, 1979).…”

Section: Effect Of Chloride On 13h]dmcm and [3h]fnz Bindingmentioning

confidence: 93%

“…Initially, the ability of anions to regulate radioligand binding to BzRs appeared to be restricted to agonists, because permeant anions (such as chloride) were reported not to affect the binding of either [3H]Ro 15-1788 (a BzR antagonist) (Mohler and Richards,198 1) or [3H]3-carboethoxy-p-carboline (a BzR inverse agonist) (Williams et al, 1981). However, Honor6 et al (1983) demonstrated that anions (chloride, iodide, and bromide) could increase the binding of the convulsant p-carboline [3H]DMCM to BzRs (Braestrup et al, 1982).…”

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confidence: 99%

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Anion Regulation of Agonist and Inverse Agonist Binding to Benzodiazepine Receptors

Evoniuk

Skolnick

1988

Journal of Neurochemistry

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Binding of the benzodiazepine inverse agonist [3H]methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate [( 3H]DMCM) and the agonist [3H]flunitrazepam [( 3H]FNZ) was compared in rat cortical membranes. Halide ions enhanced [3H]DMCM binding three- to fourfold, increasing both the apparent affinity and the number of binding sites for this radioligand. The effect was present at both 0 and 37 degrees C. In contrast, the magnitude of halide stimulation of [3H]FNZ binding was much smaller, resulting solely from an increase in the apparent affinity for this radioligand, and was not observed at 37 degrees C. The potencies but not the efficacies of a series of anions to stimulate both [3H]DMCM and [3H]FNZ binding to benzodiazepine receptors were highly correlated with their relative permeabilities through gamma-aminobutyric acid (GABA)-gated chloride channels. Two stress paradigms (10 min of immobilization or ambient-temperature swim stress), previously shown to increase significantly the magnitude of halide-stimulated [3H]FNZ binding, did not significantly affect [3H]DMCM binding. Phospholipase A2 treatment of cortical membrane preparations was equipotent in preventing the stimulatory effect of chloride on both [3H]DMCM and [3H]FNZ binding. These data strongly suggest that anions modify the binding of [3H]DMCM and [3H]FNZ by acting at a common anion binding site that is an integral component of the GABA/benzodiazepine receptor chloride channel complex.

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“…The β-carboline, methyl-6,7-dimethoxy-4-ethyl-β-carboline (DMCM), has a high affinity for the BZ binding site (Sieghart, 1995), and it acts at this site as an inverse agonist (Hono e et al, 1983). In a heterologous expression system, the action of DMCM (10 −6 M) on α1,β2,γ2 GABA A Rs increased the EC 50 for GABA greater than five-fold (Campo-Soria et al, 2006), indicating an allosteric alteration of GABA A Rs and antagonism of GABA activity.…”

Section: Introductionmentioning

confidence: 99%

GABAA receptors implicated in REM sleep control express a benzodiazepine binding site

2013

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It has been reported that non-subtype-selective GABAA receptor antagonists injected into the nucleus pontis oralis (PnO) of rats induced long-lasting increases in REM sleep. Characteristics of these REM sleep increases were identical to those resulting from injection of muscarinic cholinergic agonists. Both actions were blocked by the muscarinic antagonist, atropine. Microdialysis of GABAA receptor antagonists into the PnO resulted in increased acetylcholine levels. These findings were consistent with GABAA receptor antagonists disinhibiting acetylcholine release in the PnO to result in an acetylcholine-mediated REM sleep induction. Direct evidence has been lacking for localization in the PnO of the specific GABAA receptor-subtypes mediating the REM sleep effects. Here, we demonstrated a dose-related, long-lasting increase in REM sleep following injection (60 nl) in the PnO of the inverse benzodiazepine agonist, methyl-6,7-dimethoxy-4-ethyl-β-carboline (DMCM, 10−2 M). REM sleep increases were greater and more consistently produced than with the non-selective antagonist gabazine, and both were blocked by atropine. Fluorescence immunohistochemistry and laser scanning confocal microscopy, colocalized in PnO vesicular acetylcholine transporter, a presynaptic marker of cholinergic boutons, with the γ2 subunit of the GABAA receptor. These data provide support for the direct action of GABA on mechanisms of acetylcholine release in the PnO. The presence of the γ2 subunit at this locus and the REM sleep induction by DMCM are consistent with binding of benzodiazepines by a GABAA receptor-subtype in control of REM sleep.

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Binding of3H-DMCM to benzodiazepine receptors; chloride dependent allosteric regulation mechanisms

Cited by 11 publications

References 30 publications

Ontogenic profile of seizures evoked by the beta-carboline DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in rats

Ontogenic profile of seizures evoked by the beta-carboline DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in rats

Anion Regulation of Agonist and Inverse Agonist Binding to Benzodiazepine Receptors

GABAA receptors implicated in REM sleep control express a benzodiazepine binding site

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