Systemic or intra-amygdala injection of a benzodiazepine (midazolam) impairs extinction but spares re-extinction of conditioned fear responses

Rats were subjected to one or two cycles of fear conditioning and extinction, injected with a benzodiazepine, midazolam, before the first or second extinction, and tested for long-term inhibition of fear responses (freezing). In Experiment 1, inhibition of context-conditioned fear was spared when midazolam was injected before the second extinction, but impaired when injected before the first. In Experiment 2, it was spared when midazolam was injected before the second extinction, but only if vehicle had been injected before the first: Inhibition was impaired when the drug was injected before both. In Experiment 3, inhibition of a discrete conditioned stimulus (CS A) was spared when midazolam was injected before its second extinction, but impaired when injected before extinction of CS A in rats that had undergone extinction of CS B. In Experiment 4, inhibition was spared when midazolam was injected into the basolateral amygdala before the second extinction, but impaired when injected before the first extinction of context-conditioned fear. The results show that midazolam impairs learning, but not relearning to inhibit fear responses, and are discussed in terms of state dependency, error correction, and memory retrieval, whereby the drug's anxiolytic effects on the second extinction reactivate and strengthen the original inhibitory memory.