Interaction between benzodiazepine and GABA-A receptors in state-dependent learning.

State-dependent learning (SDL) induced by benzodiazepine (BDZ) and GABA-A agonists was investigated in the step-through passive avoidance task in rats. Pre-training injection of diazepam or muscimol dose-dependently reduced step-through latency in the test session conducted 24 hr after the training. Injection of either drug before both the training and test sessions, however, failed to reduce the latency. The results show that passive avoidance failures induced by pre-training injections of diazepam and muscimol are due to SDL. In contrast to diazepam and muscimol, baclofen induced no SDL. Diazepam and muscimol were found to substitute for each other in producing SDL. The failure of learning performance in SDL (dissociation in SDL) induced by diazepam was blocked by flumazenil and picrotoxin but not by bicuculline injected before the training session, whereas dissociation in SDL induced by muscimol was blocked by flumazenil, bicuculline and picrotoxin. On the other hand, the success of learning performance in SDL (non-dissociation in SDL) induced by diazepam was blocked by flumazenil, bicuculline and picrotoxin injected before the test session, whereas non-dissociation in SDL induced by muscimol was blocked by bicuculline and picrotoxin but not by flumazenil. These results demonstrate that 1) BDZ and GABA-A agonists produce a common drug state, but, 2) roles of each receptor in SDL might be different, i.e., BDZ receptors for dissociation in SDL and GABA-A receptors for non-dissociation in SDL, and 3) chloride ion channels are essential for the induction of SDL by BDZ and GABA-A agonists.