Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.
Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.
McKernan
R M
RM
Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. Ruth_McKernan@Merck.com
Rosahl
T W
TW
Reynolds
D S
DS
Sur
C
C
Wafford
K A
KA
Atack
J R
JR
Farrar
S
S
Myers
J
J
Cook
G
G
Ferris
P
P
Garrett
L
L
Bristow
L
L
Marshall
G
G
Macaulay
A
A
Brown
N
N
Howell
O
O
Moore
K W
KW
Carling
R W
RW
Street
L J
LJ
Castro
J L
JL
Ragan
C I
CI
Dawson
G R
GR
Whiting
P J
PJ
D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D001386:Azides / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000819:agonists / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000493:pharmacokinetics; D005464:Fluorobenzenes / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001386:Azides; D005464:Fluorobenzenes; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D008024:Ligands; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines; D005442:Flumazenil; C409903:L 838,417; C042957:Ro 15-4513; D003975:Diazepam