DOPAMINE-LINKED PHOSPHOINOSITIDE METABOLISM IN BRAIN

我们最近观察到，多巴胺刺激产生 肌醇磷脂在大鼠脑内的第二信使。多巴胺能效应 被选择性多巴胺D1受体激动剂SKF38393模拟，以及 被选择性的D1受体拮抗剂SCH23390阻断，但不被 选择性D2受体拮抗剂舒必利。此外，刺激性 观察SKF38393对纹状体、海马区、额叶的影响 大脑皮层和杏仁核，这是大脑中含有显著水平的D1的区域 受体，但不在小脑。有趣的是，杏仁核 对SKF38393诱导的肌醇磷脂有明显的敏感性 在我们的研究中，先前已经证明水解物中含有类D_1 不与多巴胺连接的腺苷刺激偶联的受体 循环酶。这些发现表明，大脑中的某些多巴胺活动 是由多巴胺受体的一个亚型介导的，该亚型选择性地 与肌醇磷脂代谢有关。这一新发现的多巴胺作用 对于理解和治疗各种不同的 与多巴胺相关的神经病理，包括精神分裂症， 帕金森症、亨廷顿舞蹈症和迟发性运动障碍。为了进一步 为了描述这种多巴胺能效应，我们设计了实验来 确定涉及的受体的特征，并可能确定其选择性 激动剂和拮抗剂，确定任何可能参与的G蛋白 转导机制，决定了二者之间的关系 肌醇磷脂代谢的刺激和多巴胺的刺激 腺苷环化酶，并确定其在脑内的区域分布 多巴胺刺激的肌醇磷脂反应。这项研究的发现 该项目将有助于为理解 多巴胺在中枢神经系统功能和功能障碍中的作用 评估并可能重新定义多巴胺相关的各种模型 神经精神障碍。

We have recently observed that dopamine stimulates the production of phosphoinositide second messengers in rat brain. The dopaminergic effect was mimicked by the selective dopamine D1 receptor agonist, SKF38393, and blocked by the selective D1 receptor antagonist, SCH23390, but not by the selective D2 receptor antagonist, sulpiride. Furthermore, the stimulatory effect of SKF38393 was observed in the striatum, hippocampus, frontal cortex, and amygdala, brain regions which contain significant levels of D1 receptors, but not in the cerebellum. Interestingly, the amygdala which exhibited a marked sensitivity to SKF38393-induced phosphoinositide hydrolysis in our studies, has previously been shown to contain D1-like receptors which do not couple to stimulation of dopamine-linked adenylate cyclase. These findings suggest that some actions of dopamine in the brain are mediated by a subtype of the dopamine receptor that is selectively coupled to phosphoinositide metabolism. This newfound action of dopamine has potential implications for the understanding and treatment of various dopamine-associated neuropathologies, including schizophrenia, parkinsonism, Huntington's chorea, and tardive dyskinesia. To further characterize this dopaminergic effect, we have devised experiments to characterize the receptor involved and possibly identify its selective agonists and antagonists, identify any G proteins that may be involved in the transduction mechanism, determine the relationship between the stimulation of phosphoinositide metabolism and dopamine-stimulated adenylate cyclase, and determine the regional brain distribution of this dopamine-stimulated phosphoinositide response. The findings of this project will help to lay a solid foundation for understanding the role of dopamine in central nervous system function and dysfunction, and for evaluating and possibly redefining various models of dopamine-associated neuropsychiatric disorders.