Fradley Rosa L, Guscott Martin R, Bull Sharlene, Hallett David J, Goodacre Simon C, Wafford Keith A, Garrett Elizabeth M, Newman Richard J, O'Meara Gillian F, Whiting Paul J, Rosahl Thomas W, Dawson Gerard R, Reynolds David S, Atack John R
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
J Psychopharmacol. 2007 Jun;21(4):384-91. doi: 10.1177/0269881106067255. Epub 2006 Nov 8.
Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity and agonist efficacy at GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 subunit. However, which of these particular subtypes are responsible for the anticonvulsant effects of diazepam remains uncertain. In the present study, we examined the ability of diazepam to reduce pentylenetetrazoLe (PTZ)-induced and maximal electroshock (MES)-induced seizures in mice containing point mutations in single (alpha1H101R, alpha2H101R or alpha5H105R) or multiple (alpha125H-->R) alpha subunits that render the resulting GABA(A) receptors diazepam-insensitive. Furthermore, the anticonvulsant properties of diazepam, the alpha1- and alpha3-selective compounds zolpidem and TP003, respectively, and the alpha2/alpha3 preferring compound TP13 were studied against PTZ-induced seizures. In the transgenic mice, no single subtype was responsible for the anticonvulsant effects of diazepam in either the PTZ or MES assay and neither the alpha3 nor alpha5 subtypes appeared to confer anticonvulsant activity. Moreover, whereas the alpha1 and alpha2 subtypes played a modest role with respect to the PTZ assay, they had a negligible role in the MES assay. With respect to subtype-selective compounds, zolpidem and TP003 had much reduced anticonvulsant efficacy relative to diazepam in both the PTZ and MES assays whereas TP13 had high anticonvulsant efficacy in the PTZ but not the MES assay. Taken together, these data not only indicate a role for alpha2-containing GABA(A) receptors in mediating PTZ and MES anticonvulsant activity but also suggest that efficacy at more than one subtype is required and that these subtypes act synergistically.
非选择性苯二氮䓬类药物，如地西泮，对含有α1、α2、α3或α5亚基的GABA(A)受体具有同等亲和力和激动剂效力。然而，这些特定亚型中哪一种介导地西泮的抗惊厥作用仍不确定。在本研究中，我们检测了地西泮对含有单个（α1H101R、α2H101R或α5H105R）或多个（α125H→R）α亚基点突变的小鼠中戊四氮（PTZ）诱导的和最大电休克（MES）诱导的癫痫发作的抑制能力，这些突变使产生的GABA(A)受体对地西泮不敏感。此外，还研究了地西泮、分别为α1和α3选择性的化合物唑吡坦和TP003以及偏好α2/α3的化合物TP13对PTZ诱导的癫痫发作的抗惊厥特性。在转基因小鼠中，无论是在PTZ还是MES试验中，没有单一亚型介导地西泮的抗惊厥作用，α3和α5亚型似乎都不具有抗惊厥活性。此外，虽然α1和α2亚型在PTZ试验中起适度作用，但在MES试验中作用可忽略不计。关于亚型选择性化合物，在PTZ和MES试验中，唑吡坦和TP003相对于地西泮的抗惊厥效力大大降低，而TP13在PTZ试验中有高抗惊厥效力，但在MES试验中则不然。综上所述，这些数据不仅表明含α2的GABA(A)受体在介导PTZ和MES抗惊厥活性中起作用，还表明需要不止一种亚型发挥效力，且这些亚型协同作用。
