Contribution of GABA(A) receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys

Abstract

Rationale: Experimental evidence suggests that the differential behavioral effects of benzodiazepines depend on their relative actions at γ-aminobutyric acid type A (GABA(A)) receptors that contain either an α1, α2, α3, or α5 subunit.

Objectives: The present study was aimed at understanding the role of α3 subunit-containing GABA(A) (α3GABA(A)) receptors by examining the behavioral pharmacology of TP003 (4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridine-3-yl]biphenyl-2-carbonitrile), which shows functional selectivity for α3GABA(A) receptors.

Methods: First, a conflict procedure was used to assess the anxiolytic-like effects of TP003 and a representative clinically available benzodiazepine. TP003 was also administered before daily periods of sucrose pellet availability to evaluate potential hyperphagic effects. In separate experiments, observable behavioral effects were used to assess the motor and sedative effects of TP003.

Results: Administration of TP003 produced robust anti-conflict effects without the rate-decreasing effects that were observed with the representative benzodiazepine. Unlike the reported effects of benzodiazepines, TP003 did not enhance palatable food consumption. However, increases in observable sleep-associated posture were induced by TP003, as were decreases in some species-typical behaviors (vocalization, locomotion, and environment-directed behaviors). When evaluated for its ability to induce a procumbent posture, TP003 failed to produce an effect.

Conclusions: Based on conflict and observation tests in monkeys, our results suggest that TP003 may have anxiolytic properties but lack ataxic, hyperphagic, and pronounced sedative effects characteristic of classical benzodiazepines. TP003 did induce myorelaxant-like effects and had relatively mild sedative effects. Collectively, these results suggest that α3GABA(A) receptors play an important role in the anxiolytic-like and motor effects of benzodiazepine-type drugs.

Figure 1

Anti-conflict effects of TP003 (a) and alprazolam (b) 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, i.v. Ordinates, response rate as responses per second. Each data point represents the mean (± S.E.M.) from three or four monkeys. Points above “V” represent data after vehicle administration. Asterisks represent significant differences relative to vehicle (Bonferroni t-tests, p<0.05).

Figure 2

Ataxia (a) and resistance (myorelaxation, b) scores of TP003 in squirrel monkeys as determined using quantitative observational procedures. Abscissae, dose of TP003 in mg/kg, i.m. Ordinates, assessment score as described in Materials and Methods section. Each data point represents the median and inter-quartile range from four monkeys. Points above “V” represent data after vehicle administration. Asterisks represent significant differences relative to vehicle (Dunn’s Q statistic, p<0.05).

Figure 3

Quantitative behavioral effects of TP003 in squirrel monkeys as determined in the observation procedure. Abscissae, dose of TP003 in mg/kg, i.m. Ordinates, pellet consumption as the mean number of sucrose pellets consumed expressed as percentage of baseline control (a) or frequency score as described in Materials and Methods section (b–f). Each data point represents the mean (± S.E.M.) from five monkeys. Points above “V” represent data after vehicle administration. Asterisks represent significant differences relative to vehicle (Bonferroni t-tests, p<0.05).