Anticonflict and reinforcing effects of triazolam + pregnanolone combinations in rhesus monkeys

Abstract

Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABA(A) receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine triazolam and the neuroactive steroid pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both triazolam and pregnanolone decreased rates of nonsuppressed responding, whereas only triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of triazolam and pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of triazolam and pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both triazolam and pregnanolone were self-administered significantly, and triazolam and pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of triazolam and pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.

Fig. 1.

Effects of triazolam and pregnanolone in the conflict procedure. Left, dose-effect curves of triazolam and pregnanolone on nonsuppressed responding. Right, dose-effect curves of triazolam and pregnanolone on suppressed responding. Abscissae, cumulative intravenous dose of triazolam or pregnanolone in milligram/kilogram. Ordinates, response rate as responses/second. Each data point represents the mean (±S.E.M.) from three monkeys. Points above V represent data after vehicle administration.

Fig. 2.

Effects of triazolam and triazolam + pregnanolone mixtures on nonsuppressed responding. Top, dose-effect curves of triazolam alone or as part of a mixture. Abscissa, cumulative intravenous dose of triazolam in milligram/kilogram. Ordinate, response rate as responses/second. Points above V represent data after vehicle administration. Bottom, isobologram of triazolam + pregnanolone mixtures. Abscissa, ED₅₀ value for triazolam in milligram/kilogram. Ordinate, ED₅₀ value for pregnanolone in milligram/kilogram. Each data point represents the mean (±S.E.M.) from three monkeys.

Fig. 3.

Dose-effect curves of triazolam alone or as part of a mixture on suppressed responding. Abscissa, cumulative intravenous dose of triazolam in milligram/kilogram. Ordinate, response rate as responses/second. Each data point represents the mean (±S.E.M.) from three monkeys. Points above V represent data after vehicle administration.

Fig. 4.

Effects of triazolam and pregnanolone on drug self-administration. Abscissa, intravenous dose of triazolam or pregnanolone in milligram/kilogram. Ordinate, drug self-administration as injections/session. Each data point represents the mean (±S.E.M.) from three monkeys. Points above V represent data after vehicle self-administration.

Fig. 5.

Effects of triazolam and triazolam + pregnanolone mixtures on drug self-administration. Top, dose-effect curves of triazolam alone or as part of a mixture. Abscissa, intravenous dose of triazolam or pregnanolone in milligram/kilogram. Ordinate, drug self-administration as injections/session. Points above V represent data after vehicle administration. Bottom, isobologram of triazolam + pregnanolone mixtures. Abscissa, ED₅₀ value for triazolam in milligram/kilogram. Ordinate, ED₅₀ value for pregnanolone in milligram/kilogram. Each data point represents the mean (±S.E.M.) from three monkeys. Asterisk represents an experimentally determined potency significantly different from the predicted additive potency (p < 0.05).