The GABAA antagonist bicuculline attenuates progesterone-induced memory impairments in middle-aged ovariectomized rats
The GABAA antagonist bicuculline attenuates progesterone-induced memory impairments in middle-aged ovariectomized rats
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DOI：
10.3389/fnagi.2015.00149
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发表时间：
2015-08-14
影响因子：
4.8
通讯作者：
Bimonte-Nelson, Heather A.
中科院分区：
文献类型：
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作者：
Braden, B. Blair;Kingston, Melissa L.;Bimonte-Nelson, Heather A.
在女性中，高水平的天然孕酮通过“母亲健忘症”现象以及对照实验与有害的认知影响有关。在老年卵巢切除（Ovx）大鼠中，孕酮已被证明会损害认知并影响认知脑区的GABA能系统。在此，我们通过与GABA（A）拮抗剂荷包牡丹碱联合治疗，试图逆转孕酮诱导的损伤，以测试GABA能系统是否是孕酮对Ovx大鼠认知功能有害影响的机制。在测试前2周开始，13月龄大鼠接受Ovx加每日媒介物、孕酮、荷包牡丹碱或孕酮+荷包牡丹碱注射。采用水辐臂迷宫评价空间工作记忆和参考记忆。在学习过程中，给予孕酮的大鼠比给予载体的大鼠产生更多的工作记忆错误，并且这种损害通过加入荷包牡丹碱而逆转。孕酮损伤是短暂的，所有动物在定期测试结束时表现相似。在测试的最后一天，给予6小时延迟以评价记忆保持。孕酮治疗的大鼠是唯一一组增加工作记忆错误的延迟相对于基线性能：再次，荷包牡丹碱的加入防止了孕酮诱导的损害。溶剂、荷包牡丹碱和孕酮+荷包牡丹碱组未受延迟损害。目前的啮齿动物研究结果证实了先前的研究报告孕激素诱导的女性和衰老的Ovx大鼠认知能力的下降。此外，数据表明，胆固醇诱导的认知障碍部分与GABA能系统有关。鉴于孕酮被包括在许多临床处方的激素疗法和避孕药中（例如，微粉化的）和作为合成类似物，有必要进一步研究以更好地理解胆甾酮诱导的认知障碍的参数和机制。
In women, high levels of natural progesterone have been associated with detrimental cognitive effects via the "maternal amnesia" phenomenon as well as in controlled experiments. In aged ovariectomized (Ovx) rats, progesterone has been shown to impair cognition and impact the GABAergic system in cognitive brain regions. Here, we tested whether the GABAergic system is a mechanism of progesterone's detrimental cognitive effects in the Ovx rat by attempting to reverse progesterone-induced impairments via concomitant treatment with the GABA(A) antagonist, bicuculline. Thirteen month old rats received Ovx plus daily vehicle, progesterone, bicuculline, or progesterone+bicuculline injections beginning 2 weeks prior to testing. The water radial-arm maze was used to evaluate spatial working and reference memory. During learning, rats administered progesterone made more working memory errors than those administered vehicle, and this impairment was reversed by the addition of bicuculline. The progesterone impairment was transient and all animals performed similarly by the end of regular testing. On the last day of testing, a 6 hour delay was administered to evaluate memory retention. Progesterone-treated rats were the only group to increase working memory errors with the delay relative to baseline performance: again, the addition of bicuculline prevented the progesterone-induced impairment. The vehicle, bicuculline, and progesterone+bicuculline groups were not impaired by the delay. The current rodent findings corroborate prior research reporting progesterone induced detriments on cognition in women and in the aging Ovx rat. Moreover, the data suggest that the progesterone-induced cognitive impairment is, in part, related to the GABAergic system. Given that progesterone is included in numerous clinically prescribed hormone therapies and contraceptives (e.g., micronized), and as synthetic analogs, further research is warranted to better understand the parameters and mechanism(s) of progesterone-induced cognitive impairments.