Benneyworth Michael A, Xiang Zixiu, Smith Randy L, Garcia Efrain E, Conn P Jeffrey, Sanders-Bush Elaine
Department of Pharmacology, Vanderbilt University School of Medicine, 8140 MRB III, Nashville, TN 37232, USA.
Mol Pharmacol. 2007 Aug;72(2):477-84. doi: 10.1124/mol.107.035170. Epub 2007 May 25.
Recent clinical studies reveal that selective agonists of group II metabotropic glutamate (mGlu) receptors have robust efficacy in treating positive and negative symptoms in patients with schizophrenia. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs and reduce the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. Because increased excitation of the medial prefrontal cortex (mPFC) has been implicated in pathophysiology of schizophrenia, the ability of group II mGlu receptor agonists to reduce hallucinogenic drug action in this region is believed to be directly related to their antipsychotic efficacy. A novel class of ligands, termed positive allosteric modulators, has recently been identified, displaying exceptional mGlu2 receptor selectivity. These compounds do not activate mGlu2 receptors directly but potentiate the ability of glutamate and other agonists to activate this receptor. We now report that the mGlu2 receptor-selective positive allosteric modulator biphenyl-indanone A (BINA) modulates excitatory neurotransmission in the mPFC and attenuates the in vivo actions of the hallucinogenic 5-HT(2A/2C) receptor agonist (-)2,5-dimethoxy-4-bromoamphetamine [(-)DOB]. BINA attenuates serotonin-induced increases in spontaneous excitatory postsynaptic currents in the mPFC, mimicking the effect of the mGlu2/3 receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV). In addition, BINA reduced (-)DOB-induced head twitch behavior and Fos expression in mPFC, effects reversed by pretreatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl) -3 - (xanth-9-yl-)propionic acid (LY341495). These data confirm the relevance of excitatory signaling in the mPFC to the behavioral actions of hallucinogens and further support the targeting of mGlu2 receptors as a novel strategy for treating glutamatergic dysfunction in schizophrenia.
近期临床研究表明，II 型代谢型谷氨酸（mGlu）受体的选择性激动剂在治疗精神分裂症患者的阳性和阴性症状方面具有强大疗效。II 型 mGlu 受体激动剂还可调节拟精神病药物的体内活性，并降低拟精神病性致幻剂增强谷氨酸能传递的能力。由于内侧前额叶皮质（mPFC）兴奋增加与精神分裂症的病理生理学有关，因此 II 型 mGlu 受体激动剂在该区域降低致幻药物作用的能力被认为与其抗精神病疗效直接相关。最近鉴定出了一类新型配体，称为正变构调节剂，它们对 mGlu2 受体具有卓越的选择性。这些化合物不会直接激活 mGlu2 受体，而是增强谷氨酸和其他激动剂激活该受体的能力。我们现在报告，mGlu2 受体选择性正变构调节剂联苯茚酮 A（BINA）可调节 mPFC 中的兴奋性神经传递，并减弱致幻性 5-HT(2A/2C)受体激动剂（-）2,5-二甲氧基-4-溴苯丙胺 [（-）DOB] 的体内作用。BINA 可减弱 5-羟色胺诱导的 mPFC 中自发性兴奋性突触后电流的增加，这与 mGlu2/3 受体激动剂（2S,2'R,3'R）-2-（2',3'-二羧基环丙基）甘氨酸（DCG-IV）的作用相似。此外，BINA 可减少（-）DOB 诱导的 mPFC 中的头部抽搐行为和 Fos 表达，mGlu2/3 受体拮抗剂 2S-2-氨基-2-（1S,2S-2-羧基环丙烷-1-基）-3-（呫吨-9-基）丙酸（LY341495）预处理可逆转这些作用。这些数据证实了 mPFC 中的兴奋性信号传导与致幻剂行为作用的相关性，并进一步支持将 mGlu2 受体作为治疗精神分裂症谷氨酸能功能障碍的新策略的靶点。
