Potency of positive gamma-aminobutyric acid(A) modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predictpotency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys

In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitu tion for midazolam was elicited by various positive gamma -aminobutyric aci d(A) (GABA(A)) modulators, including the benzodiazepines (BZs) triazolam, m idazolam, and diazepam; the BZ(1)-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 mo nkeys discriminating flumazenil (0.32 mg/kg s.c.) from vehicle, these posit ive GABA(A) modulators shifted the flumazenil dose-effect function to the r ight, i.e., attenuated diazepam withdrawal. The potency of positive GABA(A) modulators to substitute for midazolam in untreated monkeys did not predic t their potency to attenuate the flumazenil stimulus in diazepam-treated mo nkeys. For instance, larger doses of BZs and BZ(1)-selective ligands were r equired to attenuate the flumazenil stimulus than to substitute for midazol am. The opposite relationship was revealed for non-BZ ligands, i.e., smalle r doses of barbiturates and a neuroactive steroid were required to attenuat e the flumazenil stimulus than to substitute for midazolam. The greater pot ency of non-BZ site ligands to attenuate diazepam withdrawal might be due t o 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 cl ear whether attenuation of BZ withdrawal is determined by subunit specifici ty or site of action on the GABA(A) receptor complex.