Changes in relative potency among positive GABA_A receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys

Rationale: Benzodiazepine treatment can result in dependence as evidenced by signs of withdrawal upon discontinuation of use. Objective: Positive GABA_A receptor modulators were examined for their capacity to attenuate flumazenil-like discriminative stimulus effects (i.e., withdrawal) that emerge upon discontinuation of chronic benzodiazepine treatment. Methods: Rhesus monkeys receiving chronic diazepam (5.6 mg^-1 kg^-1 24 h^-1 p.o.) discriminated flumazenil (0.1 mg/kg s.c.) from vehicle. Results: Upon discontinuation of diazepam treatment, responding switched from the vehicle to the flumazenil lever, although at different times among monkeys. The shorter-acting benzodiazepine lorazepam (3.2 mg^-1 kg^-1 8 h^-1) was substituted for diazepam and, 11 h after lorazepam, monkeys consistently responded on the flumazenil lever. Flumazenil-lever responding after acute lorazepam deprivation was attenuated not only by benzodiazepines (lorazepam and midazolam) but also by positive GABA_A receptor modulators acting at neuroactive steroid (pregnanolone and alfaxalone) and barbiturate sites (pentobarbital). Deprivation-induced responding on the flumazenil lever was not attenuated by low efficacy positive GABA_A modulators (bretazenil and L-838,417) or non-GABA_A receptor ligands (ketamine and cocaine). Neuroactive steroids were relatively more potent than other positive GABA_A receptor modulators in attenuating deprivation-induced flumazenil-lever responding, as compared to their relative potency in monkeys discriminating midazolam and otherwise not receiving benzodiazepine treatment. Conclusions: These results suggest that positive GABA_A receptor modulators acting at different sites attenuate withdrawal induced by discontinuation of benzodiazepine treatment, consistent with previous studies suggesting that the same compounds attenuate flumazenil-precipitated withdrawal. Differences in the relative potency of positive modulators as a function of acute versus chronic benzodiazepine treatment suggest that neuroactive steroids, in particular, are especially potent in benzodiazepine-dependent animals.