Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat
Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat
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DOI：
10.1007/s002130000471
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发表时间：
2000-07-01
影响因子：
3.4
通讯作者：
Frye, CA
中科院分区：
文献类型：
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作者：
Bitran, D;Foley, M;Frye, CA
理由和目标：刺激脑中的线粒体苯二氮卓受体（MBR）激活神经类固醇的合成，所述神经类固醇可充当GABA受体复合物的正调节剂。别孕烯醇酮是一种有效的抗焦虑、抗惊厥、镇静和催眠GABA能神经类固醇。在向背侧海马中显微注射后测定FGIN 1-27（MBR激动剂）的抗焦虑样作用。方法：双侧注射0、1.25、2.5或5 μ g FGIN 1-27后，在成年雄性大鼠中评估高架十字迷宫中的行为。还在接受海马内共施用20 ng印防己毒素、5 μ g氟马西尼或200 ng PK 11195的动物中测定了FGIN 1-27的行为效应。在用10 mg/kg 4-MA（一种5 α-还原酶抑制剂）全身预处理的动物中，测量了FGIN 1-27对高架十字迷宫和电击探针埋藏试验中行为的影响。在用4-MA预处理并接受海马内注射FGIN 1-27的单独动物组中测量别孕烯醇酮的海马和血浆水平。结果：海马内注射FGIN 1-27在十字迷宫和电击探针埋藏试验中产生抗焦虑样作用。FGIN 1-27也增加了别孕烯醇酮的海马和血液水平。FGIN 1-27的抗焦虑样作用被PK 11195减弱，并被印防己毒素和4-MA预处理阻断，但不受氟马西尼预处理的影响。FGIN 1-27的神经类固醇生成作用也被4-MA消除。结论：海马中MBR的激活导致别孕烯醇酮的合成，别孕烯醇酮是一种增强GABAA受体功能的抗焦虑神经类固醇。
Rationale and objectives: Stimulation of the mitochondrial benzodiazepine receptor (MBR) in the brain activates the synthesis of neurosteroids that can act as positive modulators of the GABA, receptor complex. Allopregnanolone is a potent anxiolytic, anticonvulsant, sedative and hypnotic GABAergic neurosteroid. The anxiolytic-like effects of FGIN 1-27, an MBR agonist, were determined after microinjection into the dorsal hippocampus. Methods: Behavior in the elevated plus-maze was assessed in adult male rats after bilateral injections of 0, 1.25, 2.5, or 5 mu g FGIN 1-27. The behavioral effects of FGIN 1-27 were also determined in animals receiving intrahippocampal co-administration of 20 ng picrotoxin, 5 mu g flumazenil, or 200 ng PK 11195. The effects of FGIN 1-27 on behavior in the elevated plus-maze and shock-probe burying test were measured in animals pretreated systemically with 10 mg/kg 4-MA, a 5 alpha-reductase inhibitor. Hippocampal and blood plasma levels of allopregnanolone were measured in separate groups of animals pretreated with 4-MA and receiving an intrahippocampal injection of FGIN 1-27. Results: Intrahippocampal injections of FGIN 1-27 produced anxiolytic-like effects in the plus-maze and in the shock-probe burying test. Hippocampal and blood levels of allopregnanolone were also increased by FGIN 1-27. The anxiolytic-like effects of FGIN 1-27 were attenuated by PK 11195 and were blocked by picrotoxin and 4-MA pretreatment, but remained unaffected by flumazenil pretreatment. The neurosteroidogenic effect of FGIN 1-27 was also eliminated by 4-MA. Conclusion: Activation of the MBR in the hippocampus leads to the synthesis of allopregnanolone, an anxiolytic neurosteroid that potentiates GABAA receptor function.