Menezes M M, Santini M A, Benvenga M J, Marek G J, Merchant K M, Mikkelsen J D, Svensson K A
Neuroscience Discovery, Eli Lilly & Company, Indianapolis, IN 46285, USA.
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark.
Neurosci J. 2013;2013:736439. doi: 10.1155/2013/736439. Epub 2013 Nov 19.
Metabotropic glutamate 2/3 (mGlu2/3) receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL) and infralimbic (IL) cortex. LY354740 (10 and 30 mg/kg, i.p.) showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3-10 mg/kg, i.p.). Because both compounds inhibit serotonin 2A receptor (5-HT2AR)-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that 5-HT2AR activation and restraint stress induce c-Fos through distinct mechanisms.
代谢型谷氨酸受体2/3（mGlu2/3）已成为潜在的治疗靶点，因为mGlu2/3受体激动剂能够调节特定突触处的兴奋性传递。LY354740和LY379268是选择性强效mGlu2/3受体激动剂，在动物模型中表现出抗焦虑和抗精神病样作用。我们比较了LY354740和LY379268在减轻束缚应激诱导的大鼠前边缘（PrL）和边缘下（IL）皮质即刻早期基因c-Fos表达方面的效果。LY354740（10和30mg/kg，腹腔注射）在大鼠皮质中显示出对应激诱导的c-Fos表达增加具有统计学意义的剂量依赖性减弱。相比之下，LY379（0.3-10mg/kg，腹腔注射）对束缚应激诱导的c-Fos上调没有影响。由于这两种化合物均抑制5-羟色胺2A受体（5-HT2AR）诱导的c-Fos表达，我们推测LY354740和LY379268具有不同的体内特性，并且5-HT2AR激活和束缚应激通过不同机制诱导c-Fos表达。
