[ 3 H]L-655,708, a Novel Ligand Selective for the Benzodiazepine Site of GABA A Receptors which Contain the α5 Subunit

Quirk, Kathleen; Blurton, Peter; Fletcher, Stephen R.; Leeson, Paul D.; Tang, Flora; Mellilo, D.; Ragan, C I; McKernan, Ruth M.

doi:10.1016/s0028-3908(96)00061-5

Cited by 169 publications

(137 citation statements)

References 11 publications

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“…CA1 PC tonic inhibitory currents are not significantly altered by compounds known to potentiate ␦-GABA A Rs (Stell et al, 2003;Wei et al, 2004), but the cellular components necessary to express functional ␦-GABA A R are present (Glykys and Mody, 2006). To assess the component mediated by ␦-GABA A Rs in these cells, we measured tonic inhibition after application of L-655,708, an ␣5-GABA A R-selective and high-affinity (Kd ϳ2.5 nM) imidazo[1,5-␣]benzodiazepine with antagonist (inverse benzodiazepine agonist) properties (Quirk et al, 1996). L-655,708 (50 nM) reduced the tonic current by 73% ( p ϭ 0.003, paired t test) ( Table 2), and 200 nM had no additional effect (67% reduction, p ϭ 0.004 paired t test; the residual currents were similar, p ϭ 0.56 unpaired t test) ( Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Also, CA1 and CA3 PCs show a residual tonic current in the mice lacking ␣5 subunits (Glykys and Mody, 2006), suggesting that other subunits could mediate tonic inhibition in these neurons. The benzodiazepine inverse agonist L-655,708 selectively blocks ␣5-GABA A Rs at nanomolar concentrations (Quirk et al, 1996), and it has been used previously in high concentrations to block currents mediated through ␣5-GABA A Rs (Caraiscos et al, 2004;Scimemi et al, 2005). To avoid possible nonspecific effects on other non-␣5-GABA A Rs we used concentrations as low as 50 nM to block ␣5 containing receptors and demonstrated that in WT CA1 PCs there is a small tonic inhibitory current mediated by receptors other that ␣5-GABA A Rs, as increasing the dose of L-655,708 (200 nM) did not have any further effects on the tonic current in CA1 PCs.…”

Section: Discussionmentioning

confidence: 99%

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Which GABA_AReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?

Glykys¹,

Mann²,

Módy³

2008

J. Neurosci.

337

347

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GABA A receptors (GABA A Rs) assembled of different subunits mediate tonic and phasic inhibition in hippocampal neurons. CA1/CA3 pyramidal cells (PCs) predominantly express ␣5 subunits whereas dentate gyrus granule cells (DGGCs) and molecular layer (ML) interneurons predominantly express ␦ subunits. Both ␣5-and ␦-containing GABA A Rs mediate tonic inhibition. We have shown previously that mice lacking ␣5 subunits (Gabra5 Ϫ/Ϫ ) have a residual tonic current in CA1/CA3 PCs because of an upregulation of ␦ subunits, but the basis of the residual tonic current in DGGCs and ML interneurons of mice lacking the ␦ subunit (Gabrd Ϫ/Ϫ ) is still unknown. We now show that wild-type DGGCs have a small tonic current mediated by ␣5 subunit-containing GABA A Rs responsible for ϳ29% of the total tonic current. To better identify the GABA A Rs mediating tonic inhibition in hippocampal neurons, we generated mice lacking both ␣5 and ␦ subunits (Gabra5/Gabrd Ϫ/Ϫ ). Recordings from CA1/CA3 PCs, DGGCs, and ML interneurons in these mice show an absence of tonic currents without compensatory changes in spontaneous IPSCs (sIPSCs), sEPSCs, and membrane resistance. The absence of tonic inhibition results in spontaneous gamma oscillations recordable in vitro in the CA3 pyramidal layer of these mice, which can be mimicked in wild-type mice by blocking ␣5 subunit-containing GABA A Rs with 50 nM L-655,708. In conclusion, depending on the cell type, the ␣5 and ␦ subunits are the principal GABA A R subunits responsible for mediating the lion's share of tonic inhibition in hippocampal neurons.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Which GABA_AReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?

Glykys¹,

Mann²,

Módy³

2008

J. Neurosci.

337

347

View full text Add to dashboard Cite

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“…GABA A R are pentameric and most of them contain a combination of at least 1a, 1b, and 1g subunit (McKernan and Whiting, 1996;Pritchett et al, 1989;Quirk et al, 1996). The a5GABA A subunit shows a high affinity for GABA as well as a restricted pattern of expression, predominately in the HPC, with less expression in the cortex and thalamus (Heldt and Ressler, 2007;Ramos et al, 2004;Sur et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

Gill

Lodge

Cook

et al. 2011

Neuropsychopharmacol

153

181

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We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline-(SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the a5 subunit of the GABA A receptor, SH-053-2 0 F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2 0 F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the a5GABA A R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following a5GABA A R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following a5GABA A R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.

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“…To investigate whether α5-containing GABA A receptors are involved in the anti-bicuculline action of imidazenil, we studied the effect of L-655,708 (a potent and selective inverse agonist that exhibits a 100-fold affinity for α5-containing GABA A receptors when compared to α1 containing receptors; Quirk et al, 1996;Atack et al, 2006) alone and in combination with imidazenil. Fig.…”

Section: L-655708 Attenuates the Anti-bicuculline Action Of Imidazenilmentioning

confidence: 99%

Imidazenil: A low efficacy agonist at α1- but high efficacy at α5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem

et al. 2008

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SUMMARYWhereas advances in the molecular biology of GABA A receptor complex using knock-out and knockin mice have been valuable in unveiling the structure, composition, receptor assembly, and several functions of different GABA A receptor subtypes, the mechanism(s) underlying benzodiazepine (BZ) tolerance and withdrawal remain poorly understood. Studies using specific GABA A receptor subunit knock-in mice suggest that tolerance to sedative action of diazepam requires long-term activation of α1 and α5 GABA A receptor subunits. We investigated the role of long-term activation of these GABA A receptor subunits during anticonvulsant tolerance using high affinity and high intrinsic efficacy ligands for GABA A receptors expressing the α5 subunit (imidazenil) or α1 subunit (Zolpidem), and a non-selective BZ recognition site ligand (diazepam). We report here that longterm activation of GABA A receptors by zolpidem and diazepam but not by imidazenil elicits anticonvulsant tolerance. Although anticonvulsant cross-tolerance occurs between diazepam and zolpidem, there is no cross-tolerance between imidazenil and diazepam or zolpidem. Furthermore, diazepam or zolpidem long-term treatment decreased the expression of mRNA encoding the α1 GABA A receptor subunit in prefrontal cortex by 43% and 20% respectively. In addition, diazepam but not zolpidem long-term treatment produced a 30% increase in the expression of the α5 GABA A receptor subunit mRNA in prefrontal cortex. In contrast, imidazenil which is devoid of anticonvulsant tolerance does not elicit significant changes in the expression of α1 or α5 GABA A receptor subunit. These findings suggest that long-term activation of GABA A receptors containing the α1 or other subunits but not the α5 receptor subunit is essential for the induction of anticonvulsant tolerance.

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[ 3 H]L-655,708, a Novel Ligand Selective for the Benzodiazepine Site of GABA A Receptors which Contain the α5 Subunit

Cited by 169 publications

References 11 publications

Which GABA_AReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?

Which GABA_AReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

Imidazenil: A low efficacy agonist at α1- but high efficacy at α5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem

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[ 3 H]L-655,708, a Novel Ligand Selective for the Benzodiazepine Site of GABA A Receptors which Contain the α5 Subunit

Cited by 169 publications

References 11 publications

Which GABAAReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?

Which GABAAReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

Imidazenil: A low efficacy agonist at α1- but high efficacy at α5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem

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Which GABA_AReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?

Which GABA_AReceptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?