The role of GABA_Aβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole

Abstract

The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive beta2 subunit (beta2N265S) to determine the role of this subunit in mediating the sedative and anticonvulsive effects of loreclezole. Sedation was assessed by measuring spontaneous locomotor activity and beam walking performance, and anticonvulsant efficacy was determined by pentylenetetrazole (PTZ) and amygdala kindling-induced seizures. The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance. However, loreclezole also failed to provide significant protection against PTZ-induced seizures in the beta2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in beta2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors.

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…This finding is similar to that reported for knock-in mice possessing a loreclezoleinsensitive GABA A β2 receptor (Groves et al, 2006). As observed here in Fmr1 knockout mice, the loreclezole-insensitive β2 receptor mice showed less loreclezole-induced sedation, as measured by spontaneous motor activity, compared to wild-type mice.…”

“…A previous study demonstrated that mutant knock-in mice containing a loreclezole-insensitive β2 subunit were significantly less protected from pentylenetetrazole-induced seizures when treated with loreclezole (Groves et al, 2006 (Pacey et al, 2009). Increased susceptibility to audiogenic seizures in knockout mice may depend more on changes in group I mGluRs (Giuffrida et al, 2005) and GABA B receptor-mediated signalling than on GABA A receptor activity.…”

“…bind to the α subunits while loreclezole is a β2/3-specific GABA A receptor agonist (Groves et al, 2006). Female Fmr1 knockout mice were exposed to a 135 dB alarm for 2 minutes and seizure susceptibility was evaluated as previously described (Pacey et al, 2009).…”

“…The doses chosen for diazepam and loreclezole in this study were examined previously in α1 and β2 knockout mice, respectively (Kralic et al, 2002;Groves et al, 2006). Three parameters were analyzed: total activity (number of beam breaks in both horizontal and vertical plane), distance travelled (in meters), and total rearing activity.…”

Molecular Targets for Antiepileptic Drug Development

“…Similarly, the ␤2/␤3 selective agent loreclezole has sedative properties. 197,198 Substantial effort has been devoted to obtaining GABA A receptor positive allosteric modulators that have reduced activity on GABA receptors containing ␣1 subunits, to avoid the sedation that is believed to be mediated by these receptors. The compounds developed so far are generally nonbenzodiazepines that bind to the benzodiazepine site on all benzodiazepine-sensitive isoforms, but at certain isoforms are partial agonists with reduced efficacy.…”