关键词: 条件性恐惧, 即刻消退缺损, 重消退, β-肾上腺素受体阻断剂, 普萘洛尔

Abstract:

One hallmark of posttraumatic stress disorder (PTSD) involves impairments in the ability to extinguish conditioned fear memory. Accumulating evidence suggests that extinction training that occurs shortly after fear conditioning is less effective than delayed extinction training in yielding long-term extinction memory, a phenomenon that is referred to as immediate extinction deficit (IED). However, unknown is whether the IED is just an aberration or continues to affect re-extinction.

This study revealed that the early extinction intervention after severe trauma may not only fail to inhibit the fear response but also act as a secondary trauma which can continually damage the ability to extinguish fear memory. Propranolol may be a good candidate to repair such damage. Our findings improve our understanding of the pathogenesis of PTSD and outcomes of an early intervention and may be helpful for selecting appropriate and effective interventions after trauma exposure and avoid secondary trauma that is caused by the intervention itself.

In Experiment 1, 32 Sprague-Dawley rats were randomly divided into four groups (Immediate-Extinction, Immediate-No Extinction, Delayed-Extinction, Delayed-No Extinction) and underwent a standard fear conditioning procedure in which they received five tone-footshock trials in chamber A. After either 1 h (immediate) or 24 h (delayed), half of the animals underwent 30 extinction trials (1^st extinction session) in chamber B where the tone was presented alone. The other half remained in chamber B without any tone or footshock (these animals served as a no-extinction control group). Twenty-four hours later, these rats underwent the 2^nd extinction session (re- extinction) in chamber B. Twenty-four hours after the 2^nd extinction session, the rats were once again returned to chamber B and tested for their fear response to four continuous tones. The fear response was assessed by freezing behavior, and the effect of the 1^st extinction session was assessed by the average freezing response across the first four trials of the 2^nd extinction session. Compared with rats in the delayed extinction group, recently conditioned rats exhibited significantly higher levels of fear in the 2^nd extinction session, although an equivalent decline in freezing was observed in both groups across the 1^st extinction session, suggesting that immediate extinction failed to maintain fear suppression the next day. Furthermore, after undergoing two extinction training sessions, rats in the immediate extinction group exhibited no significant reduction of freezing compared with the non-extinguished control during the retention test, suggesting that the deficit reappeared during re-extinction.

The aim of Experiment 2 was to investigate whether the deficit that was induced by immediate extinction could be rescued by the β-adrenergic receptor antagonist propranolol. In Experiment 2, 20 Sprague-Dawley rats underwent the same procedures as the immediate extinction groups in Experiment 1, with the exception that they received saline or propranolol (10 mg/kg, i.p.) within minutes after fear conditioning. We found that one injection of propranolol immediately after fear acquisition rescued the deficit of re-extinction but not immediate extinction.

Key words: fear conditioning, immediate extinction deficit, re-extinction, β-noradrenergic receptor antagonist, propranolol