Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure

• Published in: Neuropharmacology Vol. 59; no. 7; pp. 612 - 618
• Main Authors: Fischer, Bradford D., Licata, Stephanie C., Edwankar, Rahul V., Wang, Zhi-Jian, Huang, Shengming, He, Xiaohui, Yu, Jianming, Zhou, Hao, Johnson, Edward M., Cook, James M., Furtmüller, Roman, Ramerstorfer, Joachim, Sieghart, Werner, Roth, Bryan L., Majumder, Samarpan, Rowlett, James K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2010
• Subjects: Alkynes - chemistry; Alkynes - pharmacology; Animals; Anti-Anxiety Agents - pharmacology; Anxiety; Anxiolytic; Benzodiazepine; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Binding, Competitive; Cell Line; Conflict; Conflict, Psychological; Diazepam - analogs & derivatives; Diazepam - chemistry; Diazepam - pharmacology; Female; GABA; GABA Modulators - pharmacology; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; In Vitro Techniques; Macaca mulatta; Male; Oocytes - drug effects; Oocytes - physiology; Patch-Clamp Techniques; Radioligand Assay; Rats; Receptors, GABA-A - metabolism; Rhesus monkey; Stereoisomerism; Structure-Activity Relationship; Xenopus laevis; GABA; Rhesus monkey; Anxiety; Conflict; Anxiolytic; Benzodiazepine
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2010.08.011

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-CH 3 and SH-053-2′F-R-CH 3 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-CH 3 and SH-053-2′F-R-CH 3 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.