Jacobson Laura H, Bettler Bernhard, Kaupmann Klemens, Cryan John F
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
J Pharmacol Exp Ther. 2006 Dec;319(3):1317-26. doi: 10.1124/jpet.106.111971. Epub 2006 Sep 21.
GABA(B) receptor agonists produce hypothermia and motor incoordination. Two GABA(B(1)) receptor subunit isoforms exist, but because of lack of specific molecular or pharmacological tools, the relevance of these isoforms in controlling basal body temperature, locomotor activity, or in vivo responses to GABA(B) receptor agonists has been unknown. Here, we used mice deficient in the GABA(B(1a)) and GABA(B(1b)) subunit isoforms to examine the influence of these isoforms on both baseline motor behavior and body temperature and on the motor-incoordinating and hypothermic responses to the GABA(B) receptor agonists l-baclofen and gamma-hydroxybutyrate (GHB). GABA(B(1b))(-/-) mice were hyperactive in a novel environment and showed slower habituation than either GABA(B(1a))(-/-) or wild-type mice. GABA(B(1b))(-/-) mice were hyperactive throughout the circadian dark phase. Hypothermia in response to l-baclofen (6 and 12 mg/kg) or GHB (1 g/kg), baclofen-induced ataxia as determined on the fixed-speed Rotarod, and GHB-induced hypolocomotion were significantly, but for the most part similarly, attenuated in both GABA(B(1a))(-/-) and GABA(B(1b))(-/-) mice. We conclude that l-baclofen and GHB are nonselective for either GABA(B(1)) receptor isoform in terms of in vivo responses. However, GABA(B(1)) receptor isoforms have distinct and different roles in mediating locomotor behavioral responses to a novel environment. Therefore, GABA(B(1a)) and GABA(B(1b)) isoforms are functionally relevant molecular variants of the GABA(B(1)) receptor subunit, which are differentially involved in specific neurophysiological processes and behaviors.
γ-氨基丁酸B（GABA(B)）受体激动剂可导致体温过低和运动不协调。存在两种GABA(B(1))受体亚基异构体，但由于缺乏特异性分子或药理学工具，这些异构体在控制基础体温、运动活性或对GABA(B)受体激动剂的体内反应中的相关性尚不清楚。在此，我们使用缺乏GABA(B(1a))和GABA(B(1b))亚基异构体的小鼠，来研究这些异构体对基线运动行为和体温以及对GABA(B)受体激动剂L-巴氯芬和γ-羟基丁酸（GHB）的运动不协调和体温过低反应的影响。GABA(B(1b))基因敲除小鼠在新环境中表现为活动过度，且比GABA(B(1a))基因敲除小鼠或野生型小鼠表现出更慢的习惯化。GABA(B(1b))基因敲除小鼠在整个昼夜节律暗期均表现为活动过度。对L-巴氯芬（6和12 mg/kg）或GHB（1 g/kg）的体温过低反应、巴氯芬诱导的共济失调（通过固定速度的转棒试验测定）以及GHB诱导的运动减少，在GABA(B(1a))基因敲除小鼠和GABA(B(1b))基因敲除小鼠中均显著减弱，但在很大程度上相似。我们得出结论，就体内反应而言，L-巴氯芬和GHB对任一GABA(B(1))受体异构体均无选择性。然而，GABA(B(1))受体异构体在介导对新环境的运动行为反应中具有不同且独特的作用。因此，GABA(B(1a))和GABA(B(1b))异构体是GABA(B(1))受体亚基的功能相关分子变体，它们分别参与特定的神经生理过程和行为。
