Potency of positive γ-aminobutyric acid_A modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys

In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitution for midazolam was elicited by various positive γ-aminobutyric acid_A (GABA_A) modulators, including the benzodiazepines (BZs) triazolam, midazolam, and diazepam; the BZ₁-selective ligands zaleplon and zolpidem; the barbiturates amobarbital and pentobarbital; and the neuroactive steroid pregnanolone. In another group of diazepam (5.6 mg/kg/day p.o.)-treated monkeys discriminating flumazenil (0.32 mg/kg s.c.) from vehicle, these positive GABA_A modulators shifted the flumazenil dose-effect function to the right, i.e., attenuated diazepam withdrawal. The potency of positive GABA_A modulators to substitute for midazolam in untreated monkeys did not predict their potency to attenuate the flumazenil stimulus in diazepam-treated monkeys. For instance, larger doses of BZs and BZ₁-selective ligands were required to attenuate the flumazenil stimulus than to substitute for midazolam. The opposite relationship was revealed for non-BZ ligands, i.e., smaller doses of barbiturates and a neuroactive steroid were required to attenuate the flumazenil stimulus than to substitute for midazolam. The greater potency of non-BZ site ligands to attenuate diazepam withdrawal might be due to actions at a subtype of GABA_A receptor not modulated by BZ site ligands, to the development of BZ tolerance without cross-tolerance to non-BZ site ligands, or to noncompetitive interactions at the GABA_A receptor complex. Thus, interactions among GABA_A modulators in BZ-dependent subjects are not predicted by their acute actions in nondependent subjects. It is not clear whether attenuation of BZ withdrawal is determined by subunit specificity or site of action on the GABA_A receptor complex.