Vinkers Christiaan H, Klanker Marianne, Groenink Lucianne, Korte S Mechiel, Cook James M, Van Linn Michael L, Hopkins Seth C, Olivier Berend
Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands.
Psychopharmacology (Berl). 2009 Jun;204(2):299-311. doi: 10.1007/s00213-009-1460-4. Epub 2009 Jan 24.
The stress-induced hyperthermia (SIH) model is an anxiety model that uses the transient rise in body temperature in response to acute stress. Benzodiazepines produce anxiolytic as well as sedative side effects through nonselective binding to GABA(A) receptor subunits. The GABA(A) receptor alpha(1) subunit is associated with sedation, whereas the GABA(A) receptor alpha(2) and alpha(3) subunits are involved in anxiolytic effects.
We therefore examined the effects of (non)subunit-selective GABA(A) receptor agonists on temperature and locomotor responses to novel cage stress.
Using telemetric monitoring of temperature and locomotor activity, we found that nonsubunit-selective GABA(A) receptor agonist diazepam as well as the alpha(3) subunit-selective receptor agonist TP003 dose-dependently attenuated SIH and locomotor responses. Administration of GABA(A) receptor alpha(1)-selective agonist zolpidem resulted in profound hypothermia and locomotor sedation. The GABA(A) receptor alpha(1)-selective antagonist betaCCt antagonized the hypothermia, but did not reverse the SIH response attenuation caused by diazepam and zolpidem. These results suggest an important regulating role for the alpha(1) subunit in thermoregulation and sedation. Ligands of extrasynaptic GABA(A) receptors such as alcohol and nonbenzodiazepine THIP attenuated the SIH response only at high doses.
The present study confirms a putative role for the GABA(A) receptor alpha(1) subunit in hypothermia and sedation and supports a role for alpha(2/3) subunit GABA(A) receptor agonists in anxiety processes. In conclusion, we show that home cage temperature and locomotor responses to novel home cage stress provide an excellent tool to assess both anxiolytic and sedative effects of various (subunit-selective) GABA(A)ergic compounds.
应激诱导的体温过高（SIH）模型是一种焦虑模型，该模型利用急性应激反应引起的体温短暂升高。苯二氮䓬类药物通过与GABA(A)受体亚基非选择性结合产生抗焦虑以及镇静副作用。GABA(A)受体α(1)亚基与镇静作用相关，而GABA(A)受体α(2)和α(3)亚基参与抗焦虑作用。
因此，我们研究了（非）亚基选择性GABA(A)受体激动剂对新笼应激引起的体温和运动反应的影响。
通过对体温和运动活动进行遥测监测，我们发现非亚基选择性GABA(A)受体激动剂地西泮以及α(3)亚基选择性受体激动剂TP003均剂量依赖性地减弱了SIH和运动反应。给予GABA(A)受体α(1)选择性激动剂唑吡坦会导致体温过低和运动性镇静。GABA(A)受体α(1)选择性拮抗剂βCCt可拮抗体温过低，但不能逆转地西泮和唑吡坦引起的SIH反应减弱。这些结果表明α(1)亚基在体温调节和镇静中具有重要的调节作用。突触外GABA(A)受体的配体，如酒精和非苯二氮䓬类药物THIP，仅在高剂量时才减弱SIH反应。
本研究证实了GABA(A)受体α(1)亚基在体温过低和镇静中的假定作用，并支持α(2/3)亚基GABA(A)受体激动剂在焦虑过程中的作用。总之，我们表明笼内温度和对新笼应激的运动反应为评估各种（亚基选择性）GABA能化合物的抗焦虑和镇静作用提供了一个极好的工具。
