Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure.
Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA(A) receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA(A) receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH₃ and SH-053-2'F-R-CH₃ at GABA(A) receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing α1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABA(A) receptors containing α1 and α5 subunits. In contrast, SH-053-2'F-S-CH₃ and SH-053-2'F-R-CH₃ produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABA(A) receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABA(A) receptor positive modulators are dependent on their relative efficacy and affinity at different GABA(A) receptor subtypes.
Fischer
Bradford D
BD
Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough, Massachusetts 01772-9102, USA. bradford_fischer@hms.harvard.edu
Licata
Stephanie C
SC
Edwankar
Rahul V
RV
Wang
Zhi-Jian
ZJ
Huang
Shengming
S
He
Xiaohui
X
Yu
Jianming
J
Zhou
Hao
H
Johnson
Edward M
EM
Cook
James M
JM
Furtmüller
Roman
R
Ramerstorfer
Joachim
J
Sieghart
Werner
W
Roth
Bryan L
BL
Majumder
Samarpan
S
Rowlett
James K
JK
D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D003220:Conflict, Psychological; D003975:Diazepam / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
C558116:8-ethynyl-6-(2'-pyridine)-4H-2,5,10b-triazabenzo(e)azulene-3-carboxylic acid ethyl ester; D000480:Alkynes; D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D007093:Imidazoles; D011963:Receptors, GABA-A; C571869:SH-053-2'F-R-CH3; D001569:Benzodiazepines; D003975:Diazepam