Abstract：
Benzodiazepines undermine the success of exposure therapy in humans with anxiety disorders, and impair the long-term memory of fear extinction (the laboratory basis of exposure therapy) in rodents. However, most rodent studies on fear extinction and benzodiazepines have been conducted in male rodents. In female rodents, the estrous cycle influences the consolidation of fear extinction memories and sensitivity to benzodiazepines. In addition, pregnancy leads to long-term changes in the neurobiological, hormonal, and behavioural features of fear extinction, as well as the responsivity to benzodiazepines. Therefore, the present experiments examined the impact of benzodiazepines on fear extinction in female rats with and without reproductive experience. Age-matched nulliparous (no reproductive experience) and primiparous (one prior reproductive experience; tested one-month post-weaning) rats received fear conditioning to a discrete cue. The next day, rats were administered the benzodiazepine diazepam (2 mg/kg, s.c), or vehicle, prior to or immediately after extinction training. Rats were then tested the next day, drug free, for extinction retention. Similar to previous findings in males, diazepam impaired extinction retention in both nulliparous and primiparous rats when administered either pre- or post-extinction training. These findings may have potential clinical implications as they suggest that benzodiazepine use in conjunction with exposure therapy may undermine long-term treatment success in women with and without reproductive experience, although this remains to be tested in human populations. Moreover, these findings are theoretically important when considered in light of previous studies showing dissociable mechanisms of fear extinction in females pre- versus post-pregnancy.
摘要：
苯二氮卓类药物破坏了焦虑症患者暴露疗法的成功，并损害啮齿动物对恐惧灭绝的长期记忆（暴露疗法的实验室基础）。然而,大多数关于恐惧灭绝和苯二氮卓类药物的啮齿动物研究都是在雄性啮齿动物中进行的。在雌性啮齿动物中，发情周期会影响恐惧灭绝记忆的巩固和对苯二氮卓类药物的敏感性。此外,怀孕会导致神经生物学的长期变化，荷尔蒙，和恐惧灭绝的行为特征，以及对苯二氮卓类药物的反应。因此,本实验研究了苯二氮卓类药物对有和没有生殖经验的雌性大鼠恐惧灭绝的影响。年龄匹配的未产（无生殖经验）和初产（先前的生殖经验；断奶后一个月进行测试）的大鼠受到了离散提示的恐惧条件。第二天,大鼠服用苯二氮卓类药物地西泮（2mg/kg，s.c),或车辆，在灭绝训练之前或之后。第二天对大鼠进行了测试，无毒品,灭绝保留。与以前在男性中的发现相似，在进行灭绝前或灭绝后训练时，地西泮会损害未产和初产大鼠的灭绝保留。这些发现可能具有潜在的临床意义，因为它们表明苯二氮卓类药物与暴露疗法结合使用可能会破坏有或没有生殖经验的女性的长期治疗成功率。尽管这仍有待在人群中进行测试。此外，从先前的研究来看，这些发现在理论上很重要，这些研究表明女性怀孕前与怀孕后恐惧消退的机制是分离的。
