Cáceda Ricardo, Kinkead Becky, Owens Michael J, Nemeroff Charles B
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci. 2005 Dec 14;25(50):11748-56. doi: 10.1523/JNEUROSCI.4282-05.2005.
Dopamine receptor agonist and NMDA receptor antagonist activation of the mesolimbic dopamine system increases locomotion and disrupts prepulse inhibition of the acoustic startle response (PPI), paradigms frequently used to study both the pharmacology of antipsychotic drugs and drugs of abuse. In rats, virally mediated overexpression of the neurotensin 1 (NT1) receptor in the nucleus accumbens antagonized d-amphetamine- and dizocilpine-induced PPI disruption, hyperlocomotion, and D-amphetamine-induced rearing. The NT receptor antagonist SR 142948A [2-[[5-(2,6-dimethoxyphenyl)-1-(4-N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride] blocked inhibition of dizocilpine-induced hyperlocomotion mediated by overexpression of the NT1 receptor. Together, these results suggest that increased nucleus accumbens NT neurotransmission, via the NT1 receptor, can decrease the effects of activation of the mesolimbic dopamine system and disruption of the glutamatergic input from limbic cortices, resembling the action of the atypical antipsychotic drug clozapine. In contrast to clozapine, virally mediated overexpression of the NT1 receptor in the nucleus accumbens had prolonged protective effects (up to 4 weeks after viral injection) without perturbing baseline PPI and locomotor behaviors. These data further confirm the NT1 receptor as the receptor mediating the antistimulant- and antipsychotic-like properties of NT and provide rationale for the development of NT1 receptor agonists as novel antipsychotic drugs. In addition, the NT1 receptor vector might be a valuable tool for understanding the mechanism of action of antipsychotic drugs and drugs of abuse and may have potential therapeutic applications.
多巴胺受体激动剂和N-甲基-D-天冬氨酸（NMDA）受体拮抗剂对中脑边缘多巴胺系统的激活会增加运动，并破坏听觉惊吓反应的前脉冲抑制（PPI），这两种范式常用于研究抗精神病药物和滥用药物的药理学。在大鼠中，伏隔核中神经降压素1（NT1）受体的病毒介导过表达可拮抗右旋苯丙胺和地佐环平诱导的PPI破坏、运动亢进以及右旋苯丙胺诱导的竖毛反应。NT受体拮抗剂SR 142948A [2-[[5-(2,6-二甲氧基苯基)-1-(4-N-(3-二甲基氨基丙基)-N-甲基氨基甲酰基)-2-异丙基苯基]-1H-吡唑-3-羰基]氨基]金刚烷-2-羧酸，盐酸盐]可阻断由NT1受体过表达介导的地佐环平诱导的运动亢进抑制。这些结果共同表明，通过NT1受体增加伏隔核NT神经传递可降低中脑边缘多巴胺系统激活的影响以及边缘皮质谷氨酸能输入的破坏，类似于非典型抗精神病药物氯氮平的作用。与氯氮平不同，伏隔核中NT1受体的病毒介导过表达具有延长的保护作用（病毒注射后长达4周），而不会干扰基线PPI和运动行为。这些数据进一步证实NT1受体是介导NT抗刺激和抗精神病样特性的受体，并为开发NT1受体激动剂作为新型抗精神病药物提供了理论依据。此外，NT1受体载体可能是理解抗精神病药物和滥用药物作用机制的有价值工具，并且可能具有潜在的治疗应用。
