Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Psychopharmacology (Berl). 2010 Jan;207(4):571-81. doi: 10.1007/s00213-009-1687-0. Epub 2009 Oct 9.
It is known that dopamine (DA) D1 receptor activation stimulates striatal nitric oxide (NO) synthesis, whereas D2 receptor activation produces the opposite effect. However, the mechanisms involved in the dopaminergic modulation of nitric oxide synthase (NOS) are unknown.
We hypothesized that the effects of DA on striatal NO signaling are dependent on ongoing glutamatergic activation of NOS. Therefore, the current study examined whether intact N-methyl-D-aspartic acid (NMDA) receptor activation is required for the dopaminergic modulation of NOS activity.
We assessed the impact of pharmacological manipulations of D1, D2, and NMDA receptors on NOS activity in the dorsal striatum and motor cortex using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Drugs were administered systemically to conscious animals and NADPH-d staining was quantified in these regions using ex vivo measurements of tissue optical density.
Administration of the neuronal NOS inhibitor N (G)-propyl-L-arginine (NPA), the D1 receptor antagonist SCH 23390, and the NMDA receptor antagonist 3-phosphonopropyl-piperazine-2-carboxylic acid (CPP) all attenuated staining selectively in the striatum. Administration of the D2 receptor agonist quinpirole decreased NADPH-d staining in both the striatum and cortex. Striatal NADPH-d staining elicited by administration of the D1 receptor agonist SKF 81297 or the D2 receptor antagonist eticlopride was attenuated by NPA, SCH 23390, and CPP pretreatment. Quinpirole pretreatment also abolished the facilitatory effect of SKF 81297.
These studies show for the first time that ongoing NMDA receptor activation is necessary for the modulation of striatal NOS activity by both facilitatory (D1 receptor activation) and inhibitory (D2 receptor activation) dopaminergic signaling mechanisms.
已知多巴胺（DA）D1 受体的激活会刺激纹状体一氧化氮（NO）的合成，而 D2 受体的激活则会产生相反的效果。然而，多巴胺能调制一氧化氮合酶（NOS）的机制尚不清楚。
我们假设 DA 对纹状体 NO 信号的影响依赖于 NOS 的持续谷氨酸激活。因此，本研究旨在探讨 NMDA 受体的完整激活是否是 DA 调制 NOS 活性的必要条件。
我们通过烟酰胺腺嘌呤二核苷酸磷酸-黄递酶（NADPH-d）组织化学评估 D1、D2 和 NMDA 受体的药理学操作对背侧纹状体和运动皮层中 NOS 活性的影响。药物通过系统给药给予清醒动物，然后使用组织光学密度的离体测量来量化这些区域的 NADPH-d 染色。
给予神经元 NOS 抑制剂 N（G）-丙基-L-精氨酸（NPA）、D1 受体拮抗剂 SCH 23390 和 NMDA 受体拮抗剂 3-膦丙基-哌嗪-2-羧酸（CPP）均可选择性地减弱纹状体的染色。给予 D2 受体激动剂喹吡罗尔可使纹状体和皮质中的 NADPH-d 染色减少。给予 D1 受体激动剂 SKF 81297 或 D2 受体拮抗剂 eticlopride 引起的纹状体 NADPH-d 染色，经 NPA、SCH 23390 和 CPP 预处理后减弱。喹吡罗尔预处理也消除了 SKF 81297 的促进作用。
这些研究首次表明，持续的 NMDA 受体激活对于两种多巴胺能信号转导机制（促进型（D1 受体激活）和抑制型（D2 受体激活））对纹状体 NOS 活性的调制都是必要的。
