Probing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine co-agonist site.
Probing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine co-agonist site.
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通过药理学操纵NMDAR甘氨酸共同激活部位来探测急性乙醇中毒的调节。
DOI：
10.1111/j.1530-0277.2012.01922.x
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Holmes A
中科院分区：
文献类型：
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作者：
Debrouse L;Hurd B;Kiselycznyk C;Plitt A;Todaro A;Mishina M;Grant SG;Camp M;Gunduz-Cinar O;Holmes A
刺激n -甲基- d -天冬氨酸受体（NMDAR）上的甘氨酸b结合位点被认为是调节乙醇（EtOH）通过NMDAR介导的行为效应的新机制，包括急性中毒。在这里，我们从药理学上在小鼠身上验证了这一假设。在C57BL/6J （B6）和129S1/SvImJ （S1）近交系小鼠中，系统注射甘氨酸b激动剂d -丝氨酸、甘氨酸转运蛋白抑制剂glt -1 ALX-5407和甘氨酸b拮抗剂l - 701324，检测其对etoh诱导的心性失调、体温过低、转直反射持续时间丧失（LORR）的影响。还测试了甘氨酸b部分激动剂d -环丝氨酸、GlyT-1抑制剂NFPS和甘氨酸b拮抗剂DCKA对etoh诱导的LORR持续时间的影响。通过在B6小鼠中联合使用d -丝氨酸与ALX-5407、d -丝氨酸与MK-801、d -丝氨酸与l - 701324、l - 701324与ALX-5407，以及在GluN2A和PSD-95 KO小鼠中联合使用d -丝氨酸，考察其对etoh诱导的LORR持续时间的相互作用效应。还测试了饮食中镁（Mg）（一种与甘氨酸b位点相互作用的元素）消耗的影响。d -丝氨酸、d -环丝氨酸、ALX-5407和NFPS都没有显著影响在所研究的任何措施或菌株上的EtOH中毒。L-701,324，而不是DCKA，剂量依赖性地增强了EtOH诱导的失调性作用，并增加了EtOH诱导的（但不是戊巴比妥诱导的）LORR持续时间。当d -丝氨酸与ALX-5407联合使用时，对etoh诱导的LORR持续时间没有交互作用。d -丝氨酸能阻止l - 701324（而不是MK-801）对LORR持续时间的etoh增强作用，而ALX-5407不能。Mg耗竭增强了B6小鼠的LORR持续时间，并对大部分S1小鼠具有致死性。GlycineB位点的激活未能在一系列措施和遗传菌株中产生假设的EtOH中毒减少，但GlycineB位点的阻断增强了EtOH中毒。这些数据表明，甘氨酸b的内源性活性可以对抗EtOH中毒，但可能很难从药理学上增强这种作用，至少在非依赖性受试者中，可能是由于甘氨酸b位点的生理饱和。
Stimulating the glycineB binding site on the N-methyl-D-aspartate receptor (NMDAR) has been proposed as a novel mechanism for modulating behavioral effects of ethanol (EtOH) that are mediated via the NMDAR, including acute intoxication. Here, we pharmacologically interrogated this hypothesis in mice. Effects of systemic injection of the glycineB agonist, D-serine, the GlyT-1 glycine transporter inhibitor, ALX-5407, and the glycineB antagonist, L-701,324, were tested for effects on EtOH-induced ataxia, hypothermia, loss of righting reflex duration (LORR) in C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mice. Effects of the glycineB partial agonist, D-cycloserine, the GlyT-1 inhibitor, NFPS, and the glycineB antagonist, DCKA, on EtOH-induced LORR duration were also tested. Interaction effects on EtOH-induced LORR duration were examined via combined treatment with D-serine and ALX-5407, D-serine and MK-801, D-serine and L-701,324, as well as L-701,324 and ALX-5407, in B6 mice, as D-serine in GluN2A and PSD-95 KO mice. The effect of dietary depletion of Magnesium (Mg), an element which interacts the glycineB site, was also tested. Neither D-serine, D-cycloserine, ALX-5407, nor NFPS significantly affected EtOH intoxication on any of the measures or strains studied. L-701,324, but not DCKA, dose-dependently potentiated the ataxia-inducing effects of EtOH and increased EtOH-induced (but not pentobarbital-induced) LORR duration. D-serine did not have interactive effects on EtOH-induced LORR duration when combined with ALX-5407. The EtOH-potentiating effects of L-701,324, but not MK-801, on LORR duration were prevented by D-serine, but not ALX-5407. Mg depletion potentiated LORR duration in B6 mice and was lethal in a large proportion of S1 mice. GlycineB site activation failed to produce the hypothesized reduction in EtOH intoxication across a range of measures and genetic strains, but blockade of the glycineB site potentiated EtOH intoxication. These data suggest endogenous activity at the glycineB opposes EtOH intoxication, but it may be difficult to pharmacologically augment this action, at least in non-dependent subjects, perhaps due to physiological saturation of the glycineB site.
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DOI：
10.1523/jneurosci.4904-07.2008
发表时间：
2008-08-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hefner K;Whittle N;Juhasz J;Norcross M;Karlsson RM;Saksida LM;Bussey TJ;Singewald N;Holmes A
通讯作者：
Holmes A
影响因子：
2.9
作者：
Boyce-Rustay, Janel M.;Cameron, Heather A.;Holmes, Andrew
通讯作者：
Holmes, Andrew
影响因子：
3.8
作者：
Dharnidharka, VR;Carney, PR
通讯作者：
Carney, PR
影响因子：
10.6
作者：
Davis, Michael;Ressler, Kerry;Richardson, Rick
通讯作者：
Richardson, Rick
DOI：
10.1038/npp.2008.182
发表时间：
2009-05
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
通讯作者：
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