DOPAMINERGIC CONTROL OF SPINAL CORD AND RESTLESS LEGS

多巴胺能控制脊髓和不宁腿

• 批准号: 6924593
• 负责人: SHAWN HOCHMAN
• 金额: $ 28.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924593
• 关键词: afferent nerve; central nervous system disorders; circadian rhythms; dopamine; dopamine receptor; dorsal root; electrocardiography; electroencephalography; electromyography; genetically modified animals; hypothalamus; in situ hybridization; laboratory mouse; leg; neuromuscular transmission; spinal cord; ventral roots

DESCRIPTION (provided by applicant): Restless legs syndrome (RLS) is a CNS disorder involving abnormal muscle sensations that are reduced during motor activity, worsen at rest, and have a marked circadian pattern. Primary treatment involves providing drugs that increase CNS dopaminergic activity, particularly activation of D2-1ike receptors. The hypothalamus controls autonomic function and circadian rhythmicity. The dorso-posterior (A11) region contains the only dopaminergic (DA) projections to spinal cord. DA fibers terminate largely in the intermediolateral column (IML) housing preganglionic sympathetic neurons and in dorsal horn regions related to muscle afferent processing. We hypothesize: (i) That a deficit in hypothalamo-spinal DA activity results in an aberrant activation of muscle afferents; directly, by reducing tonic inhibition of afferent input, and; indirectly, via a disinhibition-induced increase in sympathetic drive to skeletal muscle afferents. (ii) That low-threshold afferent activity (e.g. during movement) presynaptically depresses high-threshold muscle afferents. (iii) That DA disinhibitory actions should peak at night, the nadir of hypothalamic circadian dopamine release. As the A11 region provides the only DA input, all spinal modulatory actions can be ascribed to its function. Hence, studies of DA modulatory actions in the in vitro spinal cord will characterize the complex cellular and network actions of hypothalamo-spinal dopamine function. First, we plan to characterize the dopamine receptor distribution in spinal cord using immunostaining and in situ hybridization techniques. We will then study 5-HT and dopamine modulation of IML neuronal excitability and whether increases in sympathetic drive facilitate muscle afferent activity and input to spinal neurons. Lastly, we will use A11 neurochemical lesioning and D3 receptor knockout mice to examine their effects on alterations in spinal cord function and relate these changes to changes in several movement-related behavioral parameters concomitant with recordings of EEG, neck & limb EMG, and EKG. The uniqueness of our proposal is the development of novel and testable hypotheses on putative spinal mechanisms causing RLS. It involves the first detailed study of DA modulation of spinal cord function and it is undertaken at behavioral, network, and cellular levels, including an attempt to develop an animal model of RLS.

描述（由申请人提供）：不宁腿综合征（RLS）是一种中枢神经系统疾病，涉及异常肌肉感觉，在运动活动时减少，休息时恶化，并具有明显的昼夜节律模式。主要治疗包括提供增加中枢神经系统多巴胺能活性的药物，特别是激活d2 -1样受体。