Potency of positive γ-aminobutyric acidA 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

被引:0
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作者
McMahon, LR
Gerak, LR
France, CP
机构
[1] Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA
[2] Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78229 USA
[3] Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol, New Orleans, LA USA
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中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitution for midazolam was elicited by various positive gamma -aminobutyric acid(A) (GABA(A)) modulators, including the benzodiazepines (BZs) triazolam, midazolam, 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 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 BZ(1)-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.
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页码:1227 / 1235
页数:9
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