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

作者：Fischer Bradford D^*; Licata Stephanie C; Edwankar Rahul V; Wang Zhi Jian; Huang Shengming; He Xiaohui; Yu Jianming; Zhou Hao; Johnson Edward M Jr; Cook James M; Furtmueller Roman; Ramerstorfer Joachim; Sieghart Werner; Roth Bryan L; Majumder Samarpan; Rowlett James K

来源：Neuropharmacology, 2010, 59(7-8): 612-618.

DOI：10.1016/j.neuropharm.2010.08.011

• Benzodiazepine
• GABA
• Anxiety
• Anxiolytic
• Rhesus monkey
• Conflict

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 alpha 1, alpha 2, alpha 3 and alpha 5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing alpha 1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing alpha 2, alpha 3 and alpha 5 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 alpha 1 and alpha 5 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 alpha 2, alpha 3 and alpha 5 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.

• 出版日期2010-12