Chronic NT69L potently prevents drug-induced disruption of prepulse inhibition without causing tolerance.
Chronic NT69L potently prevents drug-induced disruption of prepulse inhibition without causing tolerance.
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DOI：
10.1016/j.bbr.2009.09.044
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发表时间：
2010-02-11
影响因子：
2.7
通讯作者：
Richelson, Elliott
中科院分区：
文献类型：
--
作者：
Briody, Siobhan;Boules, Mona;Oliveros, Alfredo;Fauq, Irfan;Richelson, Elliott
NT 69 L是一种具有抗精神病样活性的神经降压素受体激动剂。NT 69 L阻断阿扑吗啡诱导的大鼠攀爬，对刻板行为没有影响，减弱d-苯丙胺诱导的多动症，并阻断惊恐反应的前脉冲抑制（PPI）的药理学诱导的破坏。NT 69 L的重复施用导致对其一些但不是全部作用的耐受性。由于精神分裂症患者需要长期治疗，因此在PPI中测试了NT 69 L的长期（21天）施用，并与长期氟哌啶醇和氯氮平治疗进行比较。Sprague-Dawley大鼠接受NT 69 L（1.0 mg/kg）的急性或每日21次皮下注射。在第1天和第21天，NT 69 L注射30分钟后用盐水、多巴胺激动剂d-苯丙胺（5.0 mg/kg）或5-羟色胺5-HT 2A拟精神病受体激动剂[1-（2，5-二甲氧基-4-碘苯基）-2-氨基丙烷] DOI（0.5 mg/kg）处理。用氟哌啶醇（1 mg/kg）或氯氮平（20 mg/kg）代替NT 69 L重复实验。急性注射NT 69 L显著阻断d-苯丙胺和DOI对PPI的破坏。与急性注射一样，NT 69 L的21次每日给药也阻断了d-苯丙胺和DOI诱导的PPI破坏。数据显示，当在惊吓反应的PPI中测试时，动物不对NT 69 L的抗精神病样作用产生耐受性。NT 69 L长期治疗的持续功效为神经降压素激动剂治疗精神分裂症和可能的以PPI缺陷为特征的其他病症的治疗用途提供了进一步的支持。NT 69 L对多巴胺能和多巴胺能神经传递系统的调节作用，这两个系统都涉及精神分裂症的病理生理进行了讨论。
NT69L is a neurotensin receptor agonist with antipsychotic-like activity. NT69L blocks apomorphine-induced climbing in rats with no effect on stereotypic behavior, attenuates d-amphetamine-induced hyperactivity, and blocks pharmacologically-induced disruption of prepulse inhibition (PPI) of the startle response. Repeated administration of NT69L results in tolerance to some, but not to all of its effects. Because schizophrenic patients require long term treatment, chronic (21-day) administration of NT69L was tested in PPI with comparisons to chronic haloperidol and clozapine treatment. Sprague-Dawley rats received acute or 21 daily, subcutaneous injections of NT69L (1.0 mg/kg). On days one and 21 the NT69L injection was followed 30 min later by treatment with either saline; the dopamine agonist, d-amphetamine (5.0 mg/kg); or the serotonin 5-HT2A psychotomimetic receptor agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] DOI (0.5 mg/kg). Experiments were repeated with either haloperidol (1 mg/kg) or clozapine (20 mg/kg) in place of NT69L. Acute injection of NT69L significantly blocked d-amphetamine and DOI disruption of PPI. As with the acute injection, 21 daily administrations of NT69L also blocked d-amphetamine- and DOI-induced disruption of PPI. The data show that animals do not develop tolerance to the antipsychotic-like effects of NT69L when tested in the PPI of the startle response. The persistent efficacy of NT69L with chronic treatment provides further support for the therapeutic use of neurotensin agonists to treat schizophrenia and possibly other disorders that are characterized by PPI deficits. The modulatory role of NT69L on the dopaminergic and serotonergic neurotransmission systems both of which are implicated in the pathophysiology of schizophrenia is discussed.
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