PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

黑质和基底神经节的药理学和生理学

• 批准号: 3760219
• 负责人: J R WALTERS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3760219
• 关键词: 6 hydroxydopamine; basal ganglia; cannabinoids; dopamine; dopamine agonists; dopamine receptor; electrophysiology; experimental brain lesion; laboratory rat; neural plasticity; neural transmission; neuropharmacology; neurophysiology; neurotransmitter metabolism; receptor expression; receptor sensitivity; single cell analysis; substantia nigra

(1) The potencies of a series of 11 highly efficacious dopamine (DA) agonists for in vivo inhibition of DA single cell firing correlate better with in vitro binding affinities at D3 than at D2 receptors in CHO cells transfected with cDNAs encoding for D3 and D2L receptors, respectively. These results support a functional contribution of the D3 receptor subtype in the autoreceptor-mediated regulation of DA cell activity. However, infusion of DA D2 and D3 receptor antisense oligonucleotides into rat substantia nigra has, to date, produced no selective modifications of firing which can be distinguished from nonselective effects. (2) In models of basal ganglia organization, DA receptor stimulation is thought to indirectly decrease neural activity in the subthalamic nucleus due to disinhibition of the globus pallidus. However, systemic administration of the nonselective DA agonist apomorphine has been found to double the average firing rate of subthalamic neurons. Two D1 agonists also increased the firing rate of subthalamic neurons, a D2-D3 agonist produced smaller effects. Local infusion of D1 agonists also stimulated pallidal activity, indicating a potential excitatory role of DA locally in the subthalamic nucleus. Investigation of possible sites of action of D1 and D2 agonists in 6-OHDA-lesioned rats through local infusions has demonstrated short-term plasticity and indicates effects vary depending on whether D1 receptors and D2-D3 are stimulated simultaneously or 5 to 10 min apart. (3) Cannabinoid receptor distribution suggests that cannabinoids may influence basal ganglia motor function by actions on the striatal output pathways. The finding that cannabinoid agonists attenuate DA agonist- induced rotation in rats with 6-OHDA-induced DA cell lesions indicate that cannabinoid receptor stimulation influences both D1- and D2-mediated processes, although D1 processes appear to be affected to a greater degree. (4) We have found a high level of AP-1 binding in the rat striatum which is enhanced after DA depletion by reserpine treatment or by 6-OHDA- induced DA cell lesion. Binding was further enhanced by combinations of D1 and D2 DA agonists in the 6-OHDA-lesioned rats but only by D1 agonists in normal rats. The observations indicate that AP-1-mediated changes in gene expression may contribute to alterations in agonist sensitivity in the striatum after DA cell lesion.

(1) 11种高效多巴胺(DA)系列的功效 体内抑制 DA 单细胞放电的激动剂具有更好的相关性 CHO 细胞中 D3 受体的体外结合亲和力高于 D2 受体 分别用编码D3和D2L受体的cDNA转染。 这些结果支持 D3 受体的功能贡献 自身受体介导的 DA 细胞活性调节的亚型。 然而，输注 DA D2 和 D3 受体反义寡核苷酸 迄今为止，尚未对大鼠黑质产生选择性 射击的修改可以与非选择性的区别 影响。 (2) 在基底节组织模型中，DA受体刺激是 被认为间接降低丘脑底核的神经活动 由于苍白球的去抑制作用。 然而，系统性 已发现非选择性 DA 激动剂阿朴吗啡的给药 使底丘脑神经元的平均放电率加倍。两种 D1 激动剂 还增加了丘脑底神经元（D2-D3 激动剂）的放电率 产生的影响较小。 D1激动剂的局部输注也受到刺激 苍白球活性，表明 DA 具有局部潜在的兴奋作用 在丘脑底核中。调查可能的作用位点 通过局部输注，D1 和 D2 激动剂作用于 6-OHDA 损伤的大鼠 表现出短期可塑性，并表明效果因情况而异 D1 受体和 D2-D3 是否同时受到刺激或 5 到 间隔10分钟。 (3) 大麻素受体分布表明大麻素可能 通过对纹状体输出的作用影响基底神经节运动功能 途径。大麻素激动剂减弱 DA 激动剂的发现- 6-OHDA 诱导的 DA 细胞损伤大鼠的诱导旋转表明 大麻素受体刺激会影响 D1 和 D2 介导的 进程，尽管 D1 进程似乎受到更大的影响 程度。 (4) 我们发现大鼠纹状体中有高水平的 AP-1 结合， 通过利血平治疗或 6-OHDA- 消除 DA 后增强 诱导DA细胞损伤。通过组合进一步增强了结合 D1 和 D2 DA 激动剂作用于 6-OHDA 损伤的大鼠，但仅受 D1 激动剂影响 在正常大鼠中。观察结果表明 AP-1 介导的变化 基因表达可能导致激动剂敏感性的改变 DA细胞损伤后的纹状体。