Enhancement of a diazepam withdrawal symptom by bicuculline and yohimbine

The role of the GABA system in producing a pentylenetetrazol-like interoceptive discriminative stimulus during withdrawal from diazepam was investigated in rats by determining the sensitivity of this system to GABAergic drugs before and after chronic treatment with diazepam. Food-restricted rats were trained to obtain a reward of food by responding on one lever following an injection of pentylenetetrazol (PTZ; 20 mg/kg) and the other lever following an injection of saline (1 ml/kg). After rats had acquired this discrimination, the effectiveness of Ro 15-1788, bicuculline and yohimbine to substitute for pentylenetetrazol was determined. Prior to chronic treatment with diazepam, rats selected the appropriate lever for saline after Ro 15-1788 and the appropriate lever for pentylenetetrazol after bicuculline (0.04-2.5 mg/kg) or yohimbine (0.16-5.0 mg/kg). Although the selection of the appropriate lever for pentylenetetrazol was dose-dependent, full substitution for pentylenetetrazol was not obtained with either drug as larger doses of bicuculline produced convulsions while the rats began to select the appropriate lever for saline after larger doses of yohimbine (bell-shaped curve). Diazepam blocked the pentylenetetrazol-like interoceptive discriminative stimulus for bicuculline. The rats were then injected with diazepam (80 mg/kg/8 hr) for 24 days. Upon termination of the administration of diazepam, the animals were tested for lever-selection following the administration of saline, Ro 15-1788 (10 mg/kg), bicuculline (0.32, 0.64 and 1.25 mg/kg) or yohimbine (0.16, 0.64 and 2.5 mg/kg). After saline, 33% of the rats selected the appropriate lever for pentylenetetrazol whereas selection of this lever was enhanced after Ro 15-1788, bicuculline or yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)