Zhang Ce, Marek Gerard J
Department of Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Connecticut, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 1;32(1):62-71. doi: 10.1016/j.pnpbp.2007.07.009. Epub 2007 Jul 20.
Glutamate plays an important role in the psychotomimetic effects of both channel blocking N-methyl D-aspartate (NMDA) receptor antagonists and hallucinogenic drugs which activate 5-hydroxytryptamine2A (5-HT2A) receptors. Previous work suggested that activation of non-NMDA ionotropic glutamate receptors mediates the effects of 5-HT-induced excitatory post-synaptic potentials/currents (EPSPs/EPSCs) when recording from layer V pyramidal cells in the rat medial pre-frontal cortex (mPFC). However, those effects are mediated by either alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate receptors of the iGluk5 subtype. To test whether activation of AMPA receptors is sufficient to mediate 5-HT-induced EPSCs, a 2,3-benzodiazepine that selectively blocks AMPA receptors was assessed. This selective AMPA receptor antagonist potently suppressed 5-HT-induced EPSCs. Since phenethylamine hallucinogens induce head shakes by activating 5-HT2A receptors in the mPFC and this action is modulated by glutamate, we also examined whether selective blockade of AMPA receptors would suppress DOI-induced head shakes. As predicted, we found that selective blockade of AMPA receptors suppressed DOI-induced head shakes. Given evidence that activation of AMPA receptors is an important downstream effect for both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens, we also tested multiple doses of DOI with a sub-anesthetic dose of MK-801. Synergistic action between these two classes of psychotomimetic drugs was demonstrated by MK-801 enhancing DOI-induced head shakes and locomotor activity. These findings expand the dependence of both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens on enhancing extracellular glutamate.
谷氨酸在通道阻断型 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和激活 5-羟色胺 2A（5-HT2A）受体的致幻药物的拟精神病效应中起重要作用。先前的研究表明，当从大鼠内侧前额叶皮质（mPFC）的 V 层锥体细胞进行记录时，非 NMDA 离子型谷氨酸受体的激活介导了 5-羟色胺诱导的兴奋性突触后电位/电流（EPSPs/EPSCs）。然而，这些效应是由 iGluk5 亚型的α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）或海人藻酸受体介导的。为了测试 AMPA 受体的激活是否足以介导 5-羟色胺诱导的 EPSCs，评估了一种选择性阻断 AMPA 受体的 2,3-苯并二氮杂䓬。这种选择性 AMPA 受体拮抗剂强烈抑制 5-羟色胺诱导的 EPSCs。由于苯乙胺类致幻剂通过激活 mPFC 中的 5-HT2A 受体诱导摇头，且这种作用受谷氨酸调节，我们还研究了 AMPA 受体的选择性阻断是否会抑制 DOI 诱导的摇头。正如预期的那样，我们发现 AMPA 受体的选择性阻断抑制了 DOI 诱导的摇头。鉴于有证据表明 AMPA 受体的激活是通道阻断型 NMDA 受体拮抗剂和苯乙胺类致幻剂的重要下游效应，我们还用亚麻醉剂量的 MK-801 测试了多剂量的 DOI。这两类拟精神病药物之间的协同作用通过 MK-801 增强 DOI 诱导的摇头和运动活性得到了证明。这些发现扩展了通道阻断型 NMDA 受体拮抗剂和苯乙胺类致幻剂对细胞外谷氨酸增强作用的依赖性。
