Department of Psychiatry, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1229, New York, NY 10029, United States.
Neurosci Lett. 2011 Apr 15;493(3):76-9. doi: 10.1016/j.neulet.2011.01.046. Epub 2011 Jan 27.
Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [(3)H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens.
致幻药物，包括三甲氧苯乙胺、裸盖菇素和麦角酸二乙基酰胺（LSD），作用于血清素 5-HT2A 受体（5-HT2AR）。代谢型谷氨酸受体 2/3（mGluR2/3）配体在调节 5-HT2AR 激活诱导的反应方面显示出疗效。5-HT2AR-mGluR2 复合物的形成表明存在一种功能相互作用，影响致幻剂调节的细胞信号通路。在这里，我们测试了致幻 5-HT2AR 激动剂在 mGluR2 敲除（mGluR2-KO）小鼠中的细胞和行为效应。将致幻剂 DOI（2mg/kg）和 LSD（0.24mg/kg）或载体通过腹膜内注射到小鼠中。在野生型和 mGluR2-KO 小鼠中测定了摇头行为反应、所有 5-HT2AR 激动剂诱导的 c-fos 表达和致幻剂特异性的 egr-2 表达。在小鼠额叶皮质膜制剂中进行了由 DOI 引起的 [(3)H] 酮色林结合位移曲线。摇头行为在 mGluR2-KO 小鼠中被消除。在 mGluR2-KO 小鼠中未检测到高亲和力结合位点的 DOI。致幻剂 DOI 诱导了野生型和 mGluR2-KO 小鼠中的 c-fos。然而，DOI 诱导的 egr-2 在 mGlu2-KO 小鼠中被消除。这些发现表明 5-HT2AR-mGluR2 复合物是致幻剂诱导的神经心理反应所必需的。
