Echeverry M B, Salgado M L, Ferreira F R, da-Silva C A, Del Bel E A
Department MEF-Physiology, FORP, University of Sao Paulo, Av. Café S/No., 14040-904, Ribeirão Preto, SP, Brazil.
Psychopharmacology (Berl). 2007 Oct;194(2):271-8. doi: 10.1007/s00213-007-0834-8. Epub 2007 Jun 26.
Catalepsy is a preclinical test that predicts extrapyramidal symptoms in humans. It models symptoms of acute extrapyramidal side effects induced at the beginning of antipsychotic treatment. Nitric oxide (NO) plays a role in a series of neurobiological functions underlying behavior. For example, inhibition of NO synthesis disrupts rodent exploratory behavior and induces catalepsy. Although several effects mediated by NO involve the activation of soluble guanylyl cyclase (sGC), the transduction mechanism of the catalepsy-inducing effect of NO has not yet been investigated.
The study was designed to test if intracerebroventricular (i.c.v.) microinjection of NO-sensitive inhibitors of sGC (NO-sGC) induces catalepsy in mice similar to that induced by NO synthase (NOS) inhibitors. Exploratory behavior was tested in the open field. In addition, the effects of a NOS inhibitor on oxidative metabolites of NO were measured in the striatum.
Drug effects were examined in the hanging-bar test after the following i.c.v. treatments: oxadiazolo-quinoxalin (ODQ, 30-300 nmol) or methylene blue (MB, 3-100 nmol), selective and nonselective sGC inhibitors, respectively, or 7-nitroindazole (7-NI, 3-90 nmol) and G-nitro-L: -arginine methyl ester (L: -NAME, 3-90 nmol), selective and nonselective neuronal NOS inhibitors. To test if the effects were related to interference with the NO system, additional groups received 7-NI (30 nmol), ODQ (100 nmol), or L-NAME (90 nmol) preceded by L: -arginine (L: -arg, 30-100 nmol, i.c.v. 30 min before). A possible interference of ODQ and 7-NI on exploratory behavior was tested in an open field. The concentration of nitrites and nitrates (NO( x )) in striatum homogenates was measured by the Griess reaction.
Both NO-sGC and NOS inhibitors induced catalepsy in mice that lasted for at least 2 h. The range of effective doses of these drugs, however, was limited, and the dose-effect curves had an inverted U shape. The cataleptic effect induced by L: -NAME was inversely correlated with NO( x ) products in the striatum. The cataleptic effect of 7-NI and ODQ was prevented by pretreatment with L: -arginine. No drug changed exploratory behavior in the open field.
This study showed that pharmacological disruption of the endogenous NO-sGC signaling in the central nervous system induces long-lasting catalepsy in mice. Moreover, the cataleptic effect of NOS inhibition correlates with the decrease in NO( x ) products formation in the striatum. The results give further support to the hypothesis that NO plays a role in motor behavior control mediated, at least in part, by cyclic guanosine monophosphate production in the striatum.
僵住症是一种预测人类锥体外系症状的临床前测试。它模拟了抗精神病药物治疗开始时诱发的急性锥体外系副作用的症状。一氧化氮（NO）在一系列行为背后的神经生物学功能中发挥作用。例如，抑制NO合成会破坏啮齿动物的探索行为并诱发僵住症。虽然由NO介导的几种效应涉及可溶性鸟苷酸环化酶（sGC）的激活，但NO诱发僵住症效应的转导机制尚未得到研究。
本研究旨在测试脑室内（i.c.v.）微量注射对sGC敏感的NO抑制剂（NO-sGC）是否会在小鼠中诱发类似于NO合酶（NOS）抑制剂诱发的僵住症。在旷场中测试探索行为。此外，在纹状体中测量了NOS抑制剂对NO氧化代谢物的影响。
在进行以下i.c.v.处理后，通过悬杆试验检查药物效果：分别为恶二唑并喹喔啉（ODQ，30 - 300 nmol）或亚甲蓝（MB，3 - 100 nmol），分别为选择性和非选择性sGC抑制剂，或7-硝基吲唑（7-NI，3 - 90 nmol）和G-硝基-L-精氨酸甲酯（L-NAME，3 - 90 nmol），选择性和非选择性神经元NOS抑制剂。为了测试这些效应是否与对NO系统的干扰有关，另外的组在给予7-NI（30 nmol）、ODQ（100 nmol）或L-NAME（90 nmol）之前30分钟通过i.c.v.给予L-精氨酸（L-arg，30 - 100 nmol）。在旷场中测试ODQ和7-NI对探索行为的可能干扰。通过格里斯反应测量纹状体匀浆中亚硝酸盐和硝酸盐（NO(x)）的浓度。
NO-sGC和NOS抑制剂均在小鼠中诱发了持续至少2小时的僵住症。然而，这些药物的有效剂量范围有限，剂量 - 效应曲线呈倒U形。L-NAME诱发的僵住症效应与纹状体中的NO(x)产物呈负相关。用L-精氨酸预处理可预防7-NI和ODQ的僵住症效应。没有药物改变旷场中的探索行为。
本研究表明，中枢神经系统内源性NO-sGC信号的药理学破坏会在小鼠中诱发持久的僵住症。此外，NOS抑制的僵住症效应与纹状体中NO(x)产物形成的减少相关。这些结果进一步支持了NO在至少部分由纹状体中环磷酸鸟苷产生介导的运动行为控制中起作用的假说。
