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)一系列11种高效多巴胺（DA）的效力 用于体内抑制DA单细胞放电的激动剂更好地关联 在CHO细胞中，与D3受体的体外结合亲和力大于与D2受体的体外结合亲和力 分别用编码D3和D2 L受体的cDNA转染。 这些结果支持D3受体的功能贡献 在自身受体介导的调节DA细胞活性的亚型。 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， 可以区别于非选择性的发射的修改 方面的影响. (2)在基底神经节组织的模型中，DA受体刺激是 被认为间接降低了丘脑底核的神经活动 因为苍白球的抑制解除 然而，系统性的 已经发现非选择性DA激动剂阿扑吗啡的给药 使丘脑底核神经元的平均放电率加倍。两种D1激动剂 也增加了底丘脑神经元的放电率，一种D2-D3激动剂 产生较小的影响。局部输注D1激动剂也刺激了 苍白球活动，表明DA局部的潜在兴奋作用 在丘脑底核。可能作用部位的调查 D1和D2激动剂在6-OHDA损伤大鼠中通过局部输注， 表现出短期的可塑性，并表明影响取决于 是否同时刺激D1受体和D2-D3，或5 - 10分钟， 相隔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- 在6-OHDA诱导的DA细胞损伤的大鼠中诱导旋转表明， 大麻素受体刺激影响D1和D2介导的 虽然D1过程似乎受到更大的影响， ℃下 (4)我们发现大鼠纹状体中AP-1结合水平很高， 利血平处理或6-OHDA- 致DA细胞损伤。通过以下组合进一步增强结合： D1和D2 DA激动剂在6-OHDA损伤大鼠中的作用，但仅通过D1激动剂 在正常的老鼠。观察结果表明，AP-1介导的变化， 基因表达可能有助于激动剂敏感性的改变， 纹状体DA细胞损伤后。