黑质网状部和腹侧被盖区神经甾体水平的局部变化改变了雄性易撤酒抽搐小鼠慢性乙醇撤酒严重程度。
Local changes in neurosteroid levels in the substantia nigra reticulata and the ventral tegmental area alter chronic ethanol withdrawal severity in male withdrawal seizure-prone mice.
机构信息
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
出版信息
Alcohol Clin Exp Res. 2013 May;37(5):784-93. doi: 10.1111/acer.12027. Epub 2012 Dec 20.
BACKGROUND
Allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA receptors (GABAA Rs) that affects ethanol (EtOH) withdrawal. Finasteride (FIN), a 5α-reductase inhibitor that blocks the formation of ALLO and other GABAergic neurosteroids, alters EtOH sensitivity. Recently, we found that Withdrawal Seizure-Prone mice from the first genetic replicate (WSP-1) exhibited behavioral tolerance to the anticonvulsant effect of intrahippocampal ALLO during EtOH withdrawal and that intrahippocampal FIN significantly increased EtOH withdrawal severity. The purpose of this study was to determine whether neurosteroid manipulations in the substantia nigra reticulata (SNR) and ventral tegmental area (VTA) produced effects during EtOH withdrawal comparable to those seen with intrahippocampal ALLO and FIN.
METHODS
Male WSP-1 mice were surgically implanted with bilateral guide cannulae aimed at the SNR or VTA at 2 weeks prior to EtOH vapor or air exposure for 72 hours. Initial studies examined the anticonvulsant effect of a single ALLO infusion (0, 100, or 400 ng/side) at a time corresponding to peak withdrawal in the air- and EtOH-exposed mice. Separate studies examined the effect of 4 FIN infusions (0 or 10 μg/side/d) during the development of physical dependence on the expression of EtOH withdrawal.
RESULTS
ALLO infusion exerted a potent anticonvulsant effect in EtOH-naïve mice, but a diminished anticonvulsant effect during EtOH withdrawal. Administration of FIN into the SNR exerted a delayed proconvulsant effect in EtOH-naïve mice, whereas infusion into the VTA increased EtOH withdrawal duration.
CONCLUSIONS
Activation of local GABAA Rs in the SNR and VTA via ALLO infusion is sufficient to exert an anticonvulsant effect in naïve mice and to produce behavioral tolerance to the anticonvulsant effect of ALLO infusion during EtOH withdrawal. Thus, EtOH withdrawal reduced sensitivity of GABAA Rs to GABAergic neurosteroids in 2 neuroanatomical substrates within the basal ganglia in WSP-1 male mice.
背景
别孕烯醇酮（ALLO）是一种有效的 γ-氨基丁酸 A 受体（GABAA Rs）正向调节剂，可影响乙醇（EtOH）戒断。非那雄胺（FIN）是一种 5α-还原酶抑制剂，可阻断 ALLO 和其他 GABA 能神经甾体的形成，改变 EtOH 的敏感性。最近，我们发现，来自第一个遗传复制的戒断性癫痫发作易感性小鼠（WSP-1）在 EtOH 戒断期间表现出对海马内 ALLO 抗惊厥作用的行为耐受性，而海马内 FIN 显著增加 EtOH 戒断的严重程度。本研究的目的是确定黑质网状部（SNR）和腹侧被盖区（VTA）中的神经甾体操作在 EtOH 戒断期间是否产生与海马内 ALLO 和 FIN 相似的效果。
方法
雄性 WSP-1 小鼠在暴露于 EtOH 蒸气或空气 72 小时前的 2 周内接受双侧导向套管手术，目的是针对 SNR 或 VTA。最初的研究检查了单次 ALLO 输注（0、100 或 400ng/侧）的抗惊厥作用，对应于空气和 EtOH 暴露小鼠戒断的峰值。单独的研究检查了在表达 EtOH 戒断时对 FIN（0 或 10μg/侧/d）的 4 次输注的影响。
结果
在 EtOH 未处理的小鼠中，ALLO 输注表现出强大的抗惊厥作用，但在 EtOH 戒断期间，其抗惊厥作用减弱。在 EtOH 未处理的小鼠中，SNR 中 FIN 的给药产生了延迟的致惊厥作用，而 VTA 中的输注则增加了 EtOH 戒断时间。
结论
通过 ALLO 输注激活 SNR 和 VTA 中的局部 GABAA Rs，足以在未处理的小鼠中发挥抗惊厥作用，并在 EtOH 戒断期间对 ALLO 输注的抗惊厥作用产生行为耐受性。因此，在 WSP-1 雄性小鼠的基底神经节的 2 个神经解剖学基质中，EtOH 戒断降低了 GABAA Rs 对 GABA 能神经甾体的敏感性。
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