Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: Evidence from animal models of sensorimotor gating
Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: Evidence from animal models of sensorimotor gating
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DOI：
10.1523/jneurosci.21-02-00601.2001
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发表时间：
2001-01-15
影响因子：
5.3
通讯作者：
Nemeroff, CB
中科院分区：
文献类型：
--
作者：
Binder, EB;Kinkead, B;Nemeroff, CB
迄今为止，没有一种可用的抗精神病药物是治愈性的，所有药物都具有显著的潜在副作用，并且尚未确定预测上级治疗能力的受体结合谱。越来越清楚的是，精神分裂症不是由单一神经递质系统的功能障碍引起的，而是由几个相互作用的系统之间的不平衡引起的。靶向神经肽神经调质系统，协调调节所有受影响的神经递质系统可能是一个有前途的新的治疗方法精神分裂症。一个相当大的数据库是一致的假设，抗精神病药物的行为，至少部分，通过增加神经肽神经降压素（NT）的合成和释放。在这份报告中，我们证明，NT神经传递是至关重要的参与抗精神病药物的行为影响，在两种模型的抗精神病药物活性：破坏前脉冲抑制的声惊吓反应（PPI）和潜伏抑制（LI）的范例。使用NT受体拮抗剂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（SR 142948 A）阻断NT神经传递可阻止LI的正常获得和氟哌啶醇诱导的LI增强。此外，SR 142948 A阻断了氟哌啶醇和非典型抗精神病药物奎替鲁对PPI缺乏的隔离饲养动物的PPI恢复作用。我们还提供了证据，缺乏NT神经传递以及左移抗精神病药物的剂量反应曲线在隔离饲养的大鼠。这些新的发现，加上以前的观察，表明神经降压素受体激动剂可能代表一类新的抗精神病药物。
To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)- N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3- carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.