Duncan Gary E, Moy Sheryl S, Lieberman Jeffrey A, Koller Beverly H
Department of Psychiatry, University of North Carolina at Chapel Hill, USA.
Pharmacol Biochem Behav. 2006 Nov;85(3):481-91. doi: 10.1016/j.pbb.2006.09.017. Epub 2006 Nov 13.
Psychotomimetic effects of NMDA antagonists in humans suggest that NMDA receptor hypofunction could contribute to the pathophysiology of schizophrenia. A mouse line that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor was generated to model endogenous NMDA hypofunction. These mutant mice show increased locomotor activity, increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. The present study examined effects of a typical antipsychotic drug, haloperidol, and two atypical antipsychotic drugs (olanzapine and risperidone) on behavioral alterations in the NR1 hypomorphic (NR1-/-) mice. Haloperidol significantly reduced activity in the wild type controls at each dose tested (0.05, 0.1, and 0.2 mg/kg). The NR1-/- mice were less sensitive to the haloperidol-induced locomotor inhibition in comparison to the NR1+/+ mice. In contrast to haloperidol, olanzapine reduced the hyperactivity in the NR1-/- mice at a dose that produced minimal effects on locomotor activity in the wild type mice. These data suggest that non-dopaminergic blocking properties of olanzapine contribute to the drug's ability to reduce hyperactivity in the NR1 deficient mice. In the PPI paradigm, haloperidol (0.5 mg/kg) did not affect the increased startle reactivity in the NR1-/- mice, but did reduce startle amplitude in the NR1+/+ mice. Haloperidol increased PPI in both the mutant and wild type strains. Unlike haloperidol, risperidone (0.3 mg/kg) and olanzapine (3 mg/kg) reduced startle magnitude in both NR1+/+ and NR1-/- mice. Like haloperidol, risperidone and olanzapine increased PPI in both NR1+/+ and NR1-/- mice. The similar effects of these atypical antipsychotic drugs in wild type mice and mice with markedly reduced NR1 expression suggest that the drugs were not working by a NMDA receptor-dependent mechanism to increase PPI. Since both haloperidol and the atypical drugs increased PPI, it is likely that D2 dopamine receptor blockade is responsible for the drug effects on sensorimotor gating.
N-甲基-D-天冬氨酸（NMDA）拮抗剂对人类的拟精神病效应表明，NMDA受体功能减退可能与精神分裂症的病理生理学有关。为模拟内源性NMDA功能减退，构建了一种表达低水平NMDA受体N-甲基-D-天冬氨酸受体1亚基（NR1）的小鼠品系。这些突变小鼠表现出运动活性增加、听觉惊吓反应增强以及听觉惊吓前脉冲抑制（PPI）缺陷。本研究考察了一种典型抗精神病药物氟哌啶醇以及两种非典型抗精神病药物（奥氮平和利培酮）对NR1低表达（NR1-/-）小鼠行为改变的影响。在每个测试剂量（0.05、0.1和0.2mg/kg）下，氟哌啶醇均显著降低野生型对照小鼠的活性。与NR1+/+小鼠相比，NR1-/-小鼠对氟哌啶醇诱导的运动抑制不太敏感。与氟哌啶醇不同，奥氮平在对野生型小鼠运动活性产生最小影响的剂量下，降低了NR1-/-小鼠的多动。这些数据表明，奥氮平的非多巴胺能阻断特性有助于该药物降低NR1缺陷小鼠多动的能力。在PPI范式中，氟哌啶醇（0.5mg/kg）未影响NR1-/-小鼠增强的惊吓反应，但确实降低了NR1+/+小鼠的惊吓幅度。氟哌啶醇增加了突变型和野生型品系小鼠的PPI。与氟哌啶醇不同，利培酮（0.3mg/kg）和奥氮平（3mg/kg）降低了NR1+/+和NR1-/-小鼠的惊吓幅度。与氟哌啶醇一样，利培酮和奥氮平增加了NR1+/+和NR1-/-小鼠的PPI。这些非典型抗精神病药物在野生型小鼠和NR1表达显著降低的小鼠中产生的相似效应表明，这些药物并非通过依赖NMDA受体的机制来增加PPI。由于氟哌啶醇和非典型药物均增加了PPI，多巴胺D2受体阻断可能是药物对感觉运动门控产生作用的原因。
