The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex
The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex
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DOI：
10.1016/j.brainres.2009.11.048
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发表时间：
2010-01-22
期刊：
影响因子：
2.9
通讯作者：
Richelson, Elliott
中科院分区：
文献类型：
--
作者：
Li, Zhimin;Boules, Mona;Richelson, Elliott
精神分裂症是一种终身的，严重的，致残的大脑疾病，需要长期药物治疗。由于目前的抗精神病药物不能提供最佳治疗，我们一直在开发新的治疗方法，重点是神经肽神经降压素（NT）的受体。NT 69 L是神经降压素（8-13）的类似物，在用于研究精神分裂症的几种基于多巴胺的动物模型中起非典型抗精神病药物的作用。另一种现有的动物模型利用NMDA/谷氨酸受体的非竞争性拮抗剂，例如拟精神病的苯环利定（PCP）。在本研究中，我们研究了NT 69 L对大鼠中PCP诱导的行为和生化变化的影响。活动室的顶部被修改以允许我们在大鼠脑中进行穿孔素微透析，同时记录大鼠PCP注射的运动活动，显著增加活动以及内侧前额叶皮层（mPFC）中去甲肾上腺素（NE）、5-HT、多巴胺（DA）和谷氨酸的细胞外浓度。用NT 69 L预处理阻断PCP诱导的活动过度以及DA、5-HT、NE、有趣且出乎意料的是，NT 69 L显著增加甘氨酸水平，而PCP对甘氨酸水平没有影响。因此，NT 69 L在用于研究精神分裂症的这种基于谷氨酸的动物模型中显示出抗精神病样作用。我们小组的先前工作表明，NT 69 L在多巴胺能和多巴胺能啮齿动物模型中也具有抗精神病样作用。这些数据表明，特别是NT 69 L和NT受体激动剂通常可用作广谱抗精神病药物
Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia Another current animal model utilizes non-competitive antagonists of the NMDA/glutamate receptor, such as the psychotomimetic phencyclidine (PCP) In the present study, we investigated the effects of NT69L on PCP-induced behavioral and biochemical changes in the rat The top of an activity chamber was modified to allow us to perforin microdialysis in rat brain, while simultaneously recording the locomotor activity of a rat PCP injection significantly increased activity as well as the extracellular concentration of norepinephrine (NE), 5-HT, dopamine (DA), and glutamate in the medial prefrontal cortex (mPFC) Pretreating with NT69L blocked the PCP-induced hyperactivity as well as the increase of DA, 5-HT, NE, and glutamate in mPFC Interestingly and unexpectedly, NT69L markedly increased glycine levels, while PCP was without effect on glycine levels Thus, NT69L showed antipsychotic-like effects in this glutamate-based animal model for studying schizophrenia Previous work from our group suggests that NT69L also has antipsychotic-like effects in dopaminergic and serotonergic rodent models Taken together, these data suggest that NT69L in particular and NT receptor agonists in general, will be useful as broad-spectrum antipsychotic drugs Published by Elsevier B V