Del Bel E A, Guimarães F S, Bermúdez-Echeverry M, Gomes M Z, Schiaveto-de-souza A, Padovan-Neto F E, Tumas V, Barion-Cavalcanti A P, Lazzarini M, Nucci-da-Silva L P, de Paula-Souza D
Department MEF Physiology, School of Odontology, Medical School, Campus USP, Ribeirao Preto, SP, Brazil.
Cell Mol Neurobiol. 2005 Mar;25(2):371-92. doi: 10.1007/s10571-005-3065-8.
The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methylester (L-NAME), N(G)-monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NO-producing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system.
本综述文章描述了表明一氧化氮（NO）对运动控制有影响的结果。我们最近的研究表明，全身注射低剂量的一氧化氮合酶（NOS，负责生成NO的酶）抑制剂，在高架十字迷宫中会产生抗焦虑作用，而高剂量则会减少迷宫探索行为。此外，NOS抑制剂会降低在旷场实验中的运动和竖毛行为。这些结果可能涉及此类化合物的运动效应，因为NOS抑制剂，如NG-硝基-L-精氨酸（L-NOARG）、N（G）-硝基-L-精氨酸甲酯（L-NAME）、N（G）-单甲基-L-精氨酸（L-NMMA）和7-硝基吲唑（7-NIO），会在小鼠中诱发僵住症。在大鼠经全身、脑室内或纹状体内给药后也发现了这种效应。急性给予L-NOARG与多巴胺D2拮抗剂氟哌啶醇具有相加的僵住症效应。WAY 100135（5-HT1a受体拮抗剂）、酮色林（5HT2a和α1肾上腺素能受体拮抗剂）和利坦色林（5-HT2a和5HT2c受体拮抗剂）也会增强僵住症。硫酸阿托品和安坦，抗胆碱能药物，可阻断L-NOARG在小鼠中诱导的僵住症。小鼠中L-NOARG的亚慢性给药会使其僵住症效应迅速产生耐受性（3天）。它还会对氟哌啶醇诱导的僵住症产生交叉耐受性。亚慢性L-NOARG治疗后，尾状核-壳核背侧、伏隔核和脚桥被盖核中NADPH-d阳性神经元的密度增加。相反，这种治疗会减少黑质致密部中NADPH-d神经元的数量。考虑到这些结果，我们认为：（i）NO可能通过干扰纹状体中的多巴胺能、5-羟色胺能和胆碱能神经传递来调节运动行为；（ii）亚慢性抑制NO合成会在与运动控制相关的脑区中诱导产生NO的神经元发生可塑性变化，并导致对氟哌啶醇僵住症效应的交叉耐受性，这增加了此类治疗可能减少与抗精神病药物相关的运动副作用的可能性。最后，最近使用实验性帕金森病模型的研究表明，NO系统与黑质纹状体通路中的神经退行性过程之间存在相互作用。这为NO的保护作用提供了证据。总之，我们的结果表明，NO可能是黑质纹状体系统生理和病理生理过程中的关键参与者。
