Swanson Chad J, Schoepp Darryle D
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
J Pharmacol Exp Ther. 2002 Dec;303(3):919-27. doi: 10.1124/jpet.102.038422.
Recent studies have indicated that the selective group II metabotropic glutamate (mGlu) receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) shares common biochemical and pharmacological effects with the atypical antipsychotic clozapine. The present study aimed to further investigate these similarities (or differences) in monoamine-depleted animals by using the phencyclidine (PCP) model. Animals were pretreated 24 h before PCP administration with (i.p.) vehicle, alpha-methyl-DL-p-tyrosine methyl ester (alpha-MPT; 400 mg/kg), or DL-p-chlorophenyl-alanine methyl ester (PCPA; 300 mg/kg) injections. alpha-MPT and PCPA pretreatment significantly and selectively reduced catecholamine (dopamine and norepinepherine) or 5-hydroxytryptamine (5-HT, serotonin) and 5-hydroxyindoleacetic acid levels, respectively, in whole brain tissue. Both LY379268 and clozapine (s.c.) blocked PCP-evoked ambulatory activity and fine movements in control, alpha-MPT-, and PCPA-treated animals. In contrast, the typical antipsychotic haloperidol (s.c.) attenuated PCP behaviors in control and PCPA-pretreated animals, but was without effect in subjects pretreated with alpha-MPT. The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate-selective antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)OH-tetrazole-6-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) attenuated locomotor activity in alpha-MPT-treated animals only, whereas the 5-HT(2A/2C)-selective antagonist ketanserin was effective at reducing ambulations and fine movements in control and alpha-MPT-treated animals. Taken together, these data indicate an important role for glutamatergic and serotonergic mechanisms for PCP-evoked behaviors in catecholamine-depleted animals and suggest that like clozapine, LY379268 is more effective than typical antipsychotics in these models. This study further supports the potential use of group II mGlu agonists as novel therapeutic agents in the treatment of schizophrenia.
最近的研究表明，选择性II型代谢型谷氨酸（mGlu）受体激动剂（-）-2-氧杂-4-氨基双环[3.1.0]己烷-4,6-二羧酸（LY379268）与非典型抗精神病药物氯氮平具有共同的生化和药理作用。本研究旨在通过使用苯环己哌啶（PCP）模型，进一步研究单胺耗竭动物中的这些相似性（或差异）。在给予PCP前24小时，给动物腹腔注射溶剂、α-甲基-DL-对酪氨酸甲酯（α-MPT；400mg/kg）或DL-对氯苯丙氨酸甲酯（PCPA；300mg/kg）进行预处理。α-MPT和PCPA预处理分别显著且选择性地降低了全脑组织中的儿茶酚胺（多巴胺和去甲肾上腺素）或5-羟色胺（5-HT，血清素）以及5-羟吲哚乙酸水平。LY379268和氯氮平（皮下注射）均可阻断PCP在对照、α-MPT和PCPA处理动物中诱发的自主活动和精细运动。相比之下，典型抗精神病药物氟哌啶醇（皮下注射）可减弱对照和PCPA预处理动物中的PCP行为，但对α-MPT预处理动物无效。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/海人藻酸选择性拮抗剂（3S,4aR,6R,8aR）-6-[2-（1（2）OH-四唑-6-基）乙基]十氢异喹啉-3-羧酸（LY293558）仅在α-MPT处理的动物中减弱运动活性，而5-HT（2A/2C）选择性拮抗剂酮色林在对照和α-MPT处理的动物中均有效降低自主活动和精细运动。综上所述，这些数据表明谷氨酸能和5-羟色胺能机制在儿茶酚胺耗竭动物中对PCP诱发行为起重要作用，并表明与氯氮平一样，LY379268在这些模型中比典型抗精神病药物更有效。本研究进一步支持了II型mGlu激动剂作为治疗精神分裂症新型治疗药物潜在用途。
