Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands.
Eur J Pharmacol. 2011 Oct 1;668(1-2):190-3. doi: 10.1016/j.ejphar.2011.06.054. Epub 2011 Jul 8.
There is increased understanding that distinct GABA(A) receptor subtypes mediate different effects of classical benzodiazepines. Here, we aimed to define the contributions of α(1)-containing subtypes of the subtype-selective GABA(A) receptor positive allosteric modulators TPA023, ocinaplon, and NG2-73 using drug discrimination. We characterized these compounds with defined subunit preferences in rats that were trained to discriminate either the non-selective benzodiazepine chlordiazepoxide (CDP, 5.0 mg/kg) or the α(1)-selective drug zolpidem (1.5 mg/kg). In short, CDP but not zolpidem generalized to the CDP cue. In contrast, zolpidem-trained rats showed opposite effects and generalized to zolpidem but not to CDP, while the response rate reducing effects of both ligands were comparable. Moreover, TPA023, lacking efficacy at the GABA(A) receptor α(1) subunit, occasioned dose-dependent CDP-appropriate responding but generalized only to around 10% to zolpidem. Both ocinaplon and NG2-73 completely generalized to both the CDP and zolpidem cue. Overall, our data confirm and extend the previous findings in rats that compounds that lack efficacy at α(1)-containing GABA(A) receptors generalize to CDP, whereas the opposite holds true for α(1)-preferential compounds, which generalize to the α(1)-selective positive allosteric modulator zolpidem. Also, our data support the hypothesis that subtle in vitro differences in α subunit efficacy and/or affinity may eventually have large consequences in vivo. Together, our data demonstrate a reliable in vivo method to determine the contribution of the subtype-selective mechanism(s) of action for novel and subtype-selective GABA(A) receptor positive allosteric modulators, suggesting that a complex activation of multiple α subunits accounts for drug discrimination between non-selective and selective GABA(A) receptor ligands.
人们越来越认识到，不同的 GABA(A) 受体亚型介导了经典苯二氮䓬类药物的不同作用。在这里，我们旨在通过药物辨别来定义亚型选择性 GABA(A) 受体正变构调节剂 TPA023、ocinaplon 和 NG2-73 中包含 α(1)亚基的亚型的贡献。我们在大鼠中用具有明确亚基偏好的这些化合物进行了特征描述，这些大鼠被训练以辨别非选择性苯二氮䓬类药物氯氮䓬（CDP，5.0mg/kg）或 α(1)-选择性药物唑吡坦（1.5mg/kg）。简而言之，CDP 而非唑吡坦概括了 CDP 的线索。相比之下，唑吡坦训练的大鼠表现出相反的效果，概括为唑吡坦而不是 CDP，而两种配体的反应率降低效果相当。此外，缺乏 GABA(A) 受体 α(1)亚基效能的 TPA023 引起剂量依赖性的 CDP 适当反应，但仅概括为唑吡坦的约 10%。ocinaplon 和 NG2-73 完全概括了 CDP 和唑吡坦的线索。总体而言，我们的数据证实并扩展了先前在大鼠中的发现，即缺乏 α(1) 亚基效能的化合物概括为 CDP，而 α(1) 优先化合物则概括为 α(1)-选择性正变构调节剂唑吡坦。此外，我们的数据支持这样一种假设，即体外 α 亚基效能和/或亲和力的细微差异最终可能在体内产生巨大影响。总之，我们的数据证明了一种可靠的体内方法来确定新型和亚型选择性 GABA(A) 受体正变构调节剂的亚型选择性作用机制的贡献，这表明对非选择性和选择性 GABA(A) 受体配体的药物辨别需要多种 α 亚基的复杂激活。
