Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor α4 subunit knockout mice
Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor α4 subunit knockout mice
复制标题
DOI：
10.1111/j.1530-0277.2007.00563.x
复制
发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Homanics, Gregg E.
中科院分区：
文献类型：
--
作者：
Chandra, Dev;Werner, David F.;Homanics, Gregg E.
背景：γ -氨基丁酸A型受体（GABA(A)-Rs）参与介导乙醇（EtOH）的一些行为效应，但具体GABA(A)-R亚基的作用尚未完全了解。GABA(A)-R α 4亚基通常与β 2/3和δ亚基合作形成突触外GABA(A)-Rs，介导张力抑制。几项体外研究表明，这些突触外GABA(A)-Rs可能与低剂量EtOH的中毒作用特别相关。在α 4亚基敲除小鼠中，强直抑制作用大大减弱，EtOH的增强作用也大大减弱。因此，我们假设，在α 4敲除小鼠中，由含有α 4的GABA(A)-Rs介导的对EtOH的行为反应会减弱。方法：研究α 4亚基敲除小鼠急性给药中/高剂量EtOH或戊四氮的行为反应。我们比较了α 4基因敲除和野生型窝鼠对EtOH的行为反应，包括升高加迷宫（0.0、1.0 g/kg EtOH）、筛选试验（1.5、2.0 g/kg）、低温（1.5、2.0 g/kg）、固定速度旋转（1.5、2.0、2.5 g/kg）、开阔场地（0.0、1.0、2.0 g/kg）、辐射甩尾（2.0 g/kg）、翻正反射丧失（3.5 g/kg）以及EtOH代谢和清除试验。对戊四唑致癫痫的敏感性也进行了分析。结果：α 4基因敲除小鼠和野生型对照组在没有EtOH治疗的情况下的基线行为和EtOH在实验中对行为的影响没有差异。相比之下，α 4基因敲除小鼠对戊四唑诱导的癫痫发作明显更敏感。结论：我们得出结论，含有α 4亚基的GABA(A)-Rs对于中/高剂量EtOH的急性行为反应不是绝对必需的，这些反应通过升高加迷宫、筛选试验、低温、固定速度旋转杆、开阔场地、辐射甩尾和右侧反射丧失试验来评估。我们进一步认为，在α 4基因敲除小鼠中，突触GABA(A)-R EtOH敏感性和功能的代偿性改变使这些发现变得复杂。
Background: gamma-Aminobutyric acid type A receptors (GABA(A)-Rs) have been implicated in mediating some of the behavioral effects of ethanol (EtOH), but the contribution of specific GABA(A)-R subunits is not yet fully understood. The GABA(A)-R alpha 4 subunit often partners with beta 2/3 and delta subunits to form extrasynaptic GABA(A)-Rs that mediate tonic inhibition. Several in vitro studies have suggested that these extrasynaptic GABA(A)-Rs may be particularly relevant to the intoxicating effects of low doses of EtOH. In alpha 4 subunit knockout mice, tonic inhibition was greatly reduced, as were the potentiating effects of EtOH. We therefore hypothesized that those behavioral responses to EtOH that are mediated by alpha 4-containing GABA(A)-Rs would be diminished in alpha 4 knockout mice.Methods: We investigated behavioral responses to acute administration of moderate/high dose EtOH or pentylenetetrazol in alpha 4 subunit knockout mice. We compared behavioral responses to EtOH in alpha 4 knockout and wild-type littermates in the elevated plus maze (0.0, 1.0 g/kg EtOH), screen test (1.5, 2.0 g/kg), hypothermia (1.5, 2.0 g/kg), fixed speed rotarod (1.5, 2.0, 2.5 g/kg), open field (0.0, 1.0, 2.0 g/kg), radiant tail flick (2.0 g/kg), loss of righting reflex (3.5 g/kg), and EtOH metabolism and clearance assays. Sensitivity to pentylenetetrazol-induced seizures was also analyzed.Results: No differences were observed between alpha 4 knockout mice and wild-type controls in terms of the baseline behavior in the absence of EtOH treatment or in the behavioral effects of EtOH in the assays tested. In contrast, alpha 4 knockout mice were significantly more sensitive to pentylenetetrazol-induced seizures.Conclusions: We conclude that GABA(A)-Rs containing the alpha 4 subunit are not absolutely required for the acute behavioral responses to moderate/high dose EtOH that were assessed with the elevated plus maze, screen test, hypothermia, fixed speed rotarod, open field, radiant tail flick, and loss of right reflex assays. We further suggest that these findings are complicated by the demonstrated compensatory alterations in synaptic GABA(A)-R EtOH sensitivity and function in alpha 4 knockout mice.