The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole.
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.
Groves
James O
JO
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. james.groves@psy.ox.ac.uk
Guscott
Martin R
MR
Hallett
David J
DJ
Rosahl
Thomas W
TW
Pike
Andrew
A
Davies
Amy
A
Wafford
Keith A
KA
Reynolds
David S
DS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D005260:Female; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017354:Point Mutation; D018079:Receptors, GABA / Q000235:genetics / Q000502:physiology*; D011963:Receptors, GABA-A; D014230:Triazoles / Q000494:pharmacology*
D000927:Anticonvulsants; C470436:Gabrb2 protein, mouse; D006993:Hypnotics and Sedatives; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D014230:Triazoles; C066440:loreclezole