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

Abstract

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.

Fig. 1

Chemical structures of diazepam, JY-XHe-053, XHe-II-053, HZ-166, SH-053-2’F-S-CH₃ and SH-053-2’F-R-CH₃.

Fig. 2

Anti-conflict effects of diazepam, JY-XHe-053, XHe-II-053 and HZ-166 in rhesus monkeys trained under a multiple schedule of food presentation (non-suppressed responding) and food + shock presentation (suppressed responding). Abscissae, cumulative intravenous dose of drug in mg/kg. Ordinates, response rate as responses per second. Each data point represents the mean (± S.E.M.) from four monkeys. Points above “V” represent data after vehicle administration. Asterisks represent significant differences relative to vehicle for suppressed responding and daggers represent significant differences relative to vehicle for non-suppressed responding (Bonferroni t-tests, p<0.05).

Fig. 3

Anti-conflict effects of SH-053-2’F-S-CH₃ and SH-053-2’F-R-CH₃ in rhesus monkeys trained under a multiple schedule of food presentation (non-suppressed responding) and food + shock presentation (suppressed responding). Abscissae, cumulative intravenous dose of drug in mg/kg. Ordinates, response rate as responses per second. Top panels, each data point represents the mean (± S.E.M.) from four monkeys. Points above “V” represent data after vehicle administration. Bottom panels, data points represent the rate of suppressed responding in individual monkeys. Dashed lines represent rates of non-suppressed responding after vehicle administration.