Evidence for GABA tolerance in barbiturate-dependent and withdrawn mice

Mice were rendered tolerant and dependent to barbital by a chronic feeding schedule of barbital over 5 weeks. The behavioural effects of muscimol, imidazole-acetic acid (ImAA), and gamma-hydroxybutyric acid (GHB) were measured in control, barbital-dependent, and mice dependent on barbital 48 hr after withdrawal of the drug. The sedative effects of the GABA-mimetics imidazole-acetic acid and muscimol were increased in dependent mice, but reduced in withdrawn mice. Subanaesthetic doses of barbital, given acutely, also increased the sedative effects of imidazole-acetic acid and muscimol but not of gamma-hydroxybutyric acid. Assay of plasma barbital levels by GLC indicated that a negligible amount of barbital was present 48 hr after withdrawal compared to levels of between 60 and 120 micrograms/ml during chronic treatment with barbital. The binding of [3H]GABA to membrane preparations from brain indicated that the values of Kd and Bmax for low affinity binding were not significantly altered in mice withdrawn from chronic treatment with barbital, but that the Kd for high affinity binding was significantly increased from 4.38 to 6.06 nM in barbital-withdrawn mice. There was no difference in the enhancement of GABA binding by pentobarbital between the two groups. It is concluded that barbital-tolerant and dependent mice are cross-tolerant to GABA and that this is possibly mediated by a change in the affinity of the GABA receptor for its ligand.