The role of GABAAβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole

The majority of inhibitory neurotransmission in the brain is mediated by the γ-aminobutyric acid (GABA) type A (GABA A ) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA A receptors containing β2 and β3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive β2 subunit (β2N265S) 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 β2N265S 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 β2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in β2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via β2-containing GABA A receptors.