Benmansour Saloua, Arroyo Luis D, Frazer Alan
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio TX, USA.
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San AntonioTX, USA; South Texas Veterans Health Care System, San AntonioTX, USA.
Front Aging Neurosci. 2016 Dec 21;8:311. doi: 10.3389/fnagi.2016.00311. eCollection 2016.
This study investigated the effect of age and that of the post-ovariectomy (OVX) time interval on the antidepressant (AD)-like effects of estradiol (E) and selective serotonin reuptake inhibitors (SSRIs) in middle-aged (10 month) OVX rats (10m-OVX). Acute or chronic effects of these treatments in 10m-OVX were compared with those (1) in young adult (4-month) OVX rats (4m-OVX) or with older (14-month) OVX rats (14m-OVX), at a short time: 2 weeks post-OVX (+2w) and (2) in 10m-OVX rats after a longer times: 4 or 8 months post-OVX (+4m or +8m). Using chronoamperometry in the CA3 region of the hippocampus, E at 20 pmol, a dose shown previously to inhibit the serotonin transporter (SERT) in 4m-OVX, had no effect in 10m-OVX+2w. A higher dose of E (40 pmol) increased T80 value, a measure of serotonin or 5-hydroxytryptamine (5-HT) clearance, and also blocked the ability of fluvoxamine to increase T80. By contrast, estradiol had no effects on SERT function in 10m-OVX+4m, even at a higher dose than 40 pmol. Fluvoxamine slowed 5-HT clearance in 10m-OVX at +2w, +4m and +8m post-OVX as it did in the 4m-OVX. Using the forced swim test, 2 weeks treatment with E (5 μg/day), a dose shown previously to induce AD-like effects in 4m-OVX, had no effect in 10m-OVX+2w. However, a higher dose (10 μg/day) of E induced an AD-like effect as demonstrated by significantly increased swimming behavior and decreased immobility. This effect was not seen in 10m-OVX+4m. By contrast, significant AD-like effects were obtained in 14m-OVX+2w, thereby demonstrating that the lack of an AD effect of E is due to the 4-month hormone withdrawal and not to an age effect. After 2 weeks treatment with the SSRI sertraline, similar AD-like effects were obtained in 10m-OVX tested at +2w, +4m or +8m post-OVX as those found in 4m-OVX. Thus, the potency of estradiol to produce effects consistent with inhibition of the SERT was not only decreased in older rats but its effects were markedly diminished the longer hormonal depletion occurred. By contrast, the ability of SSRIs to inhibit the SERT was not affected either by age or the length of hormonal depletion.
本研究调查了年龄以及卵巢切除术后（OVX）时间间隔对中年（10个月）卵巢切除大鼠（10m - OVX）中雌二醇（E）和选择性5-羟色胺再摄取抑制剂（SSRIs）的抗抑郁（AD）样效应的影响。将这些处理对10m - OVX大鼠的急性或慢性效应与以下情况进行比较：（1）在年轻成年（4个月）卵巢切除大鼠（4m - OVX）或老年（14个月）卵巢切除大鼠（14m - OVX）中，在短时间：卵巢切除术后2周（+2w）时的效应，以及（2）在10m - OVX大鼠卵巢切除术后较长时间：4或8个月（+4m或+8m）时的效应。使用海马CA3区的计时电流法，20 pmol的E（先前显示该剂量可抑制4m - OVX中的5-羟色胺转运体（SERT））对10m - OVX + 2w大鼠没有影响。更高剂量的E（40 pmol）增加了T80值（5-羟色胺或5-羟色胺（5-HT）清除率的指标），并且还阻断了氟伏沙明增加T80的能力。相比之下，即使剂量高于40 pmol，雌二醇对10m - OVX + 4m大鼠的SERT功能也没有影响。氟伏沙明在10m - OVX大鼠卵巢切除术后+2w、+4m和+8m时减缓了5-HT清除率，与在4m - OVX大鼠中的情况相同。使用强迫游泳试验，以先前显示可在4m - OVX大鼠中诱导AD样效应的剂量E（5μg/天）进行2周治疗，对10m - OVX + 2w大鼠没有影响。然而，更高剂量（10μg/天）的E诱导了AD样效应，表现为游泳行为显著增加和不动时间减少。在10m - OVX + 4m大鼠中未观察到这种效应。相比之下，在14m - OVX + 2w大鼠中获得了显著的AD样效应，从而表明E缺乏AD效应是由于4个月的激素撤减，而不是年龄效应。在用SSRI舍曲林治疗2周后，在10m - OVX大鼠卵巢切除术后+2w、+4m或+8m时测试获得了与在4m - OVX大鼠中相似的AD样效应。因此，雌二醇产生与抑制SERT一致的效应的效力不仅在老年大鼠中降低，而且随着激素耗竭时间延长其效应明显减弱。相比之下，SSRIs抑制SERT的能力不受年龄或激素耗竭时间长度的影响。
