Department of Pharmacology, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, Brazil.
Behav Brain Res. 2011 Mar 1;217(2):416-23. doi: 10.1016/j.bbr.2010.11.016. Epub 2010 Nov 11.
Cognitive and attentional deficits in schizophrenia include impairment of the sensorimotor filter as measured by prepulse inhibition (PPI). In this way, the study of animals that naturally present low PPI responses could be a useful approach for screening new antipsychotic drugs. Several pieces of evidence suggest that dopamine and nitric oxide (NO) can modulate PPI but their role in those animals is unknown.
The aim of this study was to investigate the role of dopamine and NO in Wistar rats with naturally low PPI response.
Male Wistar rats with low PPI responses received an i.p. injection of the antipsychotics haloperidol (0.1, 0.3 or 1mg/kg) or clozapine (0.5, 1.5 or 5mg/kg), the anxiolytic diazepam (1 or 3mg/kg) or the NO synthase (NOS) inhibitors, N(G)- nitro-l-arginine (l-NOARG; 40mg/kg, acutely or sub-chronically) or 7-Nitroindazole (7-NI; 3, 10 or 30mg/kg). All animals were submitted to the PPI test 1h after injection. Striatal and cortical dopamine, DOPAC, and noradrenaline levels of rats with low PPI responses were compared to rats with normal PPI responses.
We found increased levels of catecholamines on the striatum and prefrontal cortex of Wistar rats with low PPI. In these animals, both antipsychotics, typical and atypical, and NOS inhibitors significantly increased PPI.
Taken together, our findings suggest that the low PPI phenotype may be driven by an overactive catecholamine system. Additionally, our results corroborate the hypothesis of dopamine and NO interaction on PPI modulation and suggest that Wistar rats with low PPI may represent an interesting non-pharmacological model to evaluate new potential antipsychotics.
精神分裂症的认知和注意力缺陷包括感觉运动过滤器的损伤，这种损伤可以通过条件性听觉惊吓反应（PPI）来测量。通过这种方式，研究那些自然 PPI 反应较低的动物可能是筛选新型抗精神病药物的一种有用方法。有几项证据表明，多巴胺和一氧化氮（NO）可以调节 PPI，但它们在这些动物中的作用尚不清楚。
本研究旨在探讨多巴胺和一氧化氮在自然 PPI 反应较低的 Wistar 大鼠中的作用。
PPI 反应较低的雄性 Wistar 大鼠接受腹腔注射抗精神病药氟哌啶醇（0.1、0.3 或 1mg/kg）或氯氮平（0.5、1.5 或 5mg/kg）、苯二氮䓬类抗焦虑药地西泮（1 或 3mg/kg）或一氧化氮合酶（NOS）抑制剂 N（G）-硝基-L-精氨酸（l-NOARG；急性或亚慢性 40mg/kg）或 7-硝基吲唑（7-NI；3、10 或 30mg/kg）。所有动物在注射后 1 小时接受 PPI 测试。与 PPI 正常的大鼠相比，PPI 反应较低的大鼠纹状体和皮质多巴胺、DOPAC 和去甲肾上腺素水平升高。
我们发现 PPI 反应较低的 Wistar 大鼠纹状体和前额叶皮质中的儿茶酚胺水平升高。在这些动物中，两种抗精神病药，典型和非典型，以及 NOS 抑制剂都显著增加了 PPI。
综上所述，我们的发现表明，低 PPI 表型可能是由过度活跃的儿茶酚胺系统驱动的。此外，我们的结果证实了多巴胺和 NO 相互作用对 PPI 调节的假设，并表明 PPI 较低的 Wistar 大鼠可能代表一种有趣的非药理学模型，可用于评估新的潜在抗精神病药物。
