School of Psychology, University of New South Wales, Sydney, NSW, 2052, Australia.
Psychopharmacology (Berl). 2023 Dec;240(12):2515-2528. doi: 10.1007/s00213-023-06446-z. Epub 2023 Aug 15.
Reproductive experience (pregnancy and motherhood) leads to long-term changes in the neurobiological and hormonal features of anxiety in rats and humans. The aim of this study was to examine whether reproductive experience alters the effects of two pharmacological treatments for anxiety, a benzodiazepine (diazepam) and a selective serotonin reuptake inhibitor (fluoxetine), on animal models of anxiety.
In Experiment 1, virgin (n = 47) and age-matched mother (n = 50) rats at 1-month post-weaning were injected with diazepam (1.3 mg/kg or 1.7 mg/kg, i.p.) or vehicle, in the proestrus (high estradiol/progesterone/allopregnanolone) or metestrus (low estradiol/progesterone/allopregnanolone) phase of the estrous cycle 30 min prior to the elevated plus maze (EPM). In Experiment 2, virgin (n = 25) and mother rats (n = 20) were administered fluoxetine (10 mg/kg) or vehicle for 2 weeks prior to being tested on a Pavlovian fear conditioning and extinction protocol, and the EPM.
Replicating past research, in virgin rats, the low dose of diazepam produced anxiolytic-like effects in proestrus, but only the high dose was anxiolytic-like in metestrus. In contrast, in mother rats, both doses of diazepam were anxiolytic-like irrespective of estrous phase. Fluoxetine produced anxiogenic-like effects in virgin rats during fear extinction and the EPM, but had no behavioural effects in mothers. In contrast, fluoxetine increased plasma corticosterone levels measured 30-min post-EPM in mothers, but not virgin rats.
Reproductive experience alters the dose responsivity and efficacy of common anti-anxiety medications in female rats. These findings highlight the importance of considering reproductive status in studies on anxiety and its treatment.
生殖经历（怀孕和母亲身份）会导致大鼠和人类焦虑的神经生物学和激素特征发生长期变化。本研究的目的是检查生殖经历是否会改变两种抗焦虑药物（苯二氮䓬类药物（地西泮）和选择性 5-羟色胺再摄取抑制剂（氟西汀））对焦虑动物模型的影响。
在实验 1 中，产后 1 个月的处女（n=47）和年龄匹配的母亲（n=50）大鼠在发情周期的发情前期（高雌二醇/孕酮/别孕烯醇酮）或动情后期（低雌二醇/孕酮/别孕烯醇酮）时，在高架十字迷宫（EPM）前 30 分钟，腹腔注射地西泮（1.3mg/kg 或 1.7mg/kg）或载体。在实验 2 中，处女（n=25）和母亲大鼠（n=20）在进行巴甫洛夫恐惧条件反射和消退协议以及 EPM 测试前，连续 2 周给予氟西汀（10mg/kg）或载体。
重复过去的研究，在处女大鼠中，低剂量的地西泮在发情前期产生抗焦虑样作用，但只有高剂量在动情后期具有抗焦虑样作用。相比之下，在母亲大鼠中，两种剂量的地西泮都具有抗焦虑样作用，而与发情期无关。氟西汀在恐惧消退和 EPM 期间在处女大鼠中产生焦虑样效应，但在母亲中没有行为效应。相比之下，氟西汀增加了母亲的血浆皮质酮水平，测量时间为 EPM 后 30 分钟，但在处女大鼠中没有。
生殖经历改变了女性大鼠常用抗焦虑药物的剂量反应性和疗效。这些发现强调了在焦虑及其治疗研究中考虑生殖状态的重要性。
