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)系列11种高效多巴胺(DA)的效力 体内抑制DA单细胞放电的激动剂相关性更好 CHO细胞D3受体与D2受体的体外结合亲和力 分别用编码D3和D2L受体的cDNA进行转染。 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 到目前为止，在大鼠黑质中还没有产生选择性 可区别于非选择性射击的改装 效果。 (2)在基底节区组织模型中，DA受体的兴奋是 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，系统性的 已发现非选择性多巴胺激动剂阿朴吗啡的给药 将丘脑下层神经元的平均放电频率提高一倍。两种D1激动剂 也增加了D2-D3激动剂丘脑底神经元的放电率 产生了较小的效果。局部输注D1激动剂也刺激了 苍白球活动，表明多巴胺在局部有潜在的兴奋作用 在丘脑底核。对可能的行动地点进行调查 6-羟基多巴胺损毁大鼠局部注射D_1和D_2激动剂 证明了短期可塑性，并表明效果视情况而定 关于D_1受体和D_2-D_3受体是同时被刺激还是5到 每隔10分钟。 (3)大麻素受体的分布表明，大麻素可以 作用于纹状体输出对基底节运动功能的影响 小路。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 大麻素受体的刺激同时影响到d1和d2介导的 进程，尽管D1进程似乎受到更大的影响 学位。 (4)我们在大鼠纹状体中发现了AP-1的高水平结合。 在利血平或6-OHDA-DA耗竭后增强 诱导DA细胞损伤。通过以下组合进一步增强了约束性 6-羟基多巴胺损毁大鼠体内的D_1和D_2多巴胺激动剂，但仅通过D_1激动剂 在正常大鼠身上。观察表明，AP-1介导的变化在 基因表达可能有助于激动剂敏感性的改变 损毁DA细胞后的纹状体。