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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems.
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Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems.

机译：长期的社会隔离增强了小鼠的微毒素癫痫发作易感性：内源性脑Allopregnanolone在GABA能系统中的上调作用。

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摘要

Allopregnanolone (ALLO, 3alpha,5alpha-tetrahydroprogesterone), a positive allosteric modulator of actions of gamma-aminobutyric acid GABA) at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: a type I 5alpha-reductase and a 3alpha-hydroxysteroid oxidoreductase. We previously demonstrated that long-term social isolation of mice caused a significant decrease in brain ALLO content via suppression of type I 5alpha-reductase and its mRNA expression. In this study, to clarify a physiological role of endogenous brain ALLO, we investigated changes in seizure susceptibility of mice following protracted social isolation and compared with those of mice treated with SKF105111 (SKF), an inhibitor of types I and II 5alpha-reductase. Social isolation of mice for 7 weeks prior to the experiments caused a significant increase of seizure susceptibility to the GABA(A) receptor antagonist picrotoxin but not to the glycine receptor antagonist strychnine or the glutamate receptor agonist kainic acid. The change in the seizure susceptibility was completely reversed by 2.5 mg/kg ip ALLO, a dose that per se had no effect on picrotoxin-induced seizure. Treatment of mice with SKF (20 mg/kg ip) also reduced a threshold dose of picrotoxin, but not that of strychnine or kainic acid, which was required to elicit seizure in group-housed mice. The effect of SKF was attenuated by ALLO (2.5 mg/kg ip). In contrast, SKF treatment had no effect on picrotoxin-induced seizure in socially isolated mice. These findings suggest that endogenous brain ALLO plays a suppressive role in seizure susceptibility via a positive modulation of GABA(A) receptor function and that social isolation enhances seizure susceptibility in mice via reduction of GABA(A) receptor function caused by a decrease of endogenous ALLO.
机译：在大脑中，黄体酮通过两种酶的顺序作用合成了异戊烷醇酮（ALLO，3α，5α-四氢孕酮）对GABA（A）受体的γ-氨基丁酸GABA作用的正变构调节剂。 -还原酶和3α-羟基类固醇氧化还原酶。我们先前证明，长期的社会隔离小鼠通过抑制I型5α-还原酶及其mRNA表达，导致大脑ALLO含量显着下降。在这项研究中，为了阐明内源性大脑ALLO的生理作用，我们调查了长期社会隔离后小鼠癫痫发作敏感性的变化，并将其与用I型和II型5α-还原酶抑制剂SKF105111（SKF）治疗的小鼠进行了比较。实验前7周对小鼠进行社会隔离导致对GABA（A）受体拮抗剂微毒素而不是对甘氨酸受体拮抗剂士的宁或谷氨酸受体激动剂海藻酸的癫痫发作敏感性显着增加。 2.5 mg / kg ip ALLO可完全逆转癫痫发作敏感性的变化，该剂量本身对微毒素诱导的癫痫发作没有影响。用SKF（20 mg / kg ip ip）处理小鼠也降低了微毒素的阈值剂量，但降低了士多宁或海藻酸的阈值剂量，这是诱发成群饲养的小鼠癫痫发作所必需的。 SKF的作用被ALLO（2.5 mg / kg ip ip）减弱。相比之下，SKF治疗对社交分离小鼠中微毒素诱导的癫痫发作没有影响。这些发现表明，内源性脑ALLO通过积极调节GABA（A）受体功能在癫痫发作易感性中起抑制作用，社会隔离通过降低内源性ALLO引起的GABA（A）受体功能的降低而增强了小鼠的癫痫易感性。 。

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