The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats.
The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats.
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DOI：
10.1016/j.neuropharm.2015.05.001
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发表时间：
2015-10
影响因子：
4.7
通讯作者：
Risbrough VB
中科院分区：
文献类型：
--
作者：
Li X;Kaczanowska K;Finn MG;Markou A;Risbrough VB
GABAB（γ-氨基丁酸B）受体可能是焦虑症的治疗靶点。在这里，我们的特点的影响GABAB受体阳性变构调节剂（PAM）BHF 177的条件和非条件的生理反应的威胁，在光增强惊吓（LES），应激诱导的高热，恐惧增强惊吓（FPS）的程序在大鼠。将BHF 177对LES的作用与GABAB受体激动剂巴氯芬和CGP 44532以及阳性对照丁螺环酮（一种在人体中具有抗焦虑活性的5-HT 1A受体部分激动剂）的作用进行比较。巴氯芬（0.4、0.9和1.25 mg/kg）和CGP 44532（0.065、0.125和0.25 mg/kg）给药具有显著的镇静活性，但不具有抗焦虑活性，反映在LES试验中惊吓反应的总体降低中。BHF 177（10、20和40 mg/kg）对LES没有影响，也没有产生总体镇静作用。然而，有趣的是，当将大鼠按LES反应高低分组时，BHF 177仅对LES反应高的大鼠具有抗焦虑样作用，而对LES反应低的大鼠没有。BHF 177还阻断了应激诱导的体温过高，但在FPS测试中对条件性恐惧反应没有影响。丁螺环酮（1和3 mg/kg）在LES和FPS试验中均具有抗焦虑作用。这些结果表明，BHF 177可以特异性减弱表现出高度焦虑状态的个体的无条件焦虑，并且比直接激动剂的镇静作用更少。因此，BHF 177或其它GABAB受体PAM可能是用于缓解在各种精神障碍中观察到的增加的焦虑的有希望的化合物，与GABAB受体激动剂相比具有上级副作用特征。
GABAB (γ-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress-induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists.