Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines.
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.
Dias
Rebecca
R
The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom. rebecca_dias@merck.com
Sheppard
Wayne F A
WF
Fradley
Rosa L
RL
Garrett
Elizabeth M
EM
Stanley
Joanna L
JL
Tye
Spencer J
SJ
Goodacre
Simon
S
Lincoln
Rachael J
RJ
Cook
Susan M
SM
Conley
Rachel
R
Hallett
David
D
Humphries
Alexander C
AC
Thompson
Sally A
SA
Wafford
Keith A
KA
Street
Leslie J
LJ
Castro
J Luis
JL
Whiting
Paul J
PJ
Rosahl
Thomas W
TW
Atack
John R
JR
McKernan
Ruth M
RM
Dawson
Gerard R
GR
Reynolds
David S
DS
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D012453:Saimiri
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; C546257:GABRA3 protein, human; C546258:Gabra3 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines