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

Abstract

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.Clinical trials have established the effectiveness of cognitivebehavioral therapy for anxiety disorders such as posttraumatic stress (Harvey et al. 2003). A component of this therapy is cue exposure in which the patient, aided by the clinician, confronts trauma-related cues in the absence of overt danger. One aim of these confrontations is to reduce, even eliminate, the ability of the trauma-related cues to elicit the fear memories that are undermining the quality of the patient's life. This aim is frequently achieved. However, the psychological processes and neural mechanisms that underlie the successes of cue exposure or that are responsible for its failures are poorly understood. Therefore, there has been much interest in laboratory models of cue exposure. One model is the extinction of Pavlovian conditioned fear responses.

Systemic or intra-amygdala infusion of the benzodiazepine, midazolam, impairs learning, but facilitates re-learning to inhibit fear responses in extinction

“…Experiment 1 replicated the previous findings of Hart et al (2009) that rats re-extinguished for 20 min under midazolam (Group Re-Ext 20min MID) failed to show impairment on the subsequent retention test, exhibiting low levels of fear similar to those shown by rats reextinguished for 20 min under vehicle (Group Re-Ext 20min VEH). Experiment 1 revealed a novel finding: Rats reextinguished for just 4 min under midazolam (Group Re-Ext 4min MID) also showed low levels of fear on the retention test, suggesting that long-term inhibition had been just as effective with a short, as with a longer, re-extinction session.…”

“…The design (see Table 1) consisted in subjecting rats to two context conditioning episodes, a brief (4 min) or longer (20 min) extinction under the drug or vehicle, and finally, a retention test. Hart et al (2009) have shown that rats given 20-min extinction under midazolam exhibited substantial levels of fear responses on the subsequent retention test, suggesting that the drug had disrupted learning inhibition. But we have not previously examined whether rats subjected to a shorter (e.g., 4 min) extinction under the drug also show substantial levels of fear responses on the subsequent test.…”

“…For example, infusion of a benzodiazepine into the amygdala reduces fear responses in rats (Helmstetter 1993;Harris and Westbrook 1995), while infusion of an antagonist increases anxiogenic responses (Sanders and Shekhar 1991). In previous work, Hart et al (2009) reported that the administration of a benzodiazepine (midazolam) prior to extinction impaired long-term inhibitory learning, but that administration of the drug prior to re-extinction failed to produce this impairment. That is, rats given a benzodiazepine before re-extinction showed low levels of fear responding on a subsequent retention test.…”

Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction

“…These neurons project to diencephalic and brainstem structures that control the behavioral, autonomic, and endocrine components of the fear response (Sah et al 2003). In addition to its key role in fear learning, the BLA is also necessary for acquisition and consolidation of extinction (Lin et al 2003;Herry et al 2006Herry et al , 2008Kim et al 2007;Sotres-Bayon et al 2007Kim and Richardson 2008;Hart et al 2009). Recent evidence (Herry et al 2008) has revealed that a distinct population of BLA neurons contributes to the inhibitory learning produced by extinction.…”

“…This view has received support from recent studies of the neural mechanisms underlying relearning to inhibit fear responses (Kim and Richardson 2008;Hart et al 2009). Relearning occurs when an extinguished CS is paired with the aversive US and the fear responses produced by that retraining are again extinguished.…”