PURINE-DOPAMINE INTERACTIONS IN A LESCH-NYHAN MODEL

LESCH-NYHAN 模型中的嘌呤-多巴胺相互作用

• 批准号: 3402407
• 负责人: GEORGE R BREESE
• 金额: $ 12.51万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3402407
• 关键词: 6 hydroxydopamine; Lesch Nyhan syndrome; adenosine; adenylate cyclase; disease /disorder model; electrophysiology; guanosine triphosphate; hypoxanthine phosphoribosyltransferase; neurochemistry; neurotoxins; newborn animals; radioassay; sympathetic nervous system

The Lesch-Nyhan syndrome (LNS) is characterized by a deficiency of the enzyme, HGPRT, motor dysfunction, mental retardation, hyperuricemia, self-mutilation behavior (SMB) and a loss of dopaminergic neurons. In rats, neonatal destruction of dopaminergic neurons with 6-hydroxy-dopamine (6-OHDA) increases susceptibility for SMB when D-1 dopamine receptors are activated, suggesting that neonatal-6-OHDA treatment is a model of the central dopamine deficiency of LNS. The present grant explores how this enzyme and altered purine mechanisms may interact with dopaminergic function. We plan to determine the relative amount of HGPRT in dopamine-containing (or other) neurons by measuring HGPRT activity after neurotoxin treatment. We will also determine if purine compounds, which accumulate in LNS, influence the function of dopaminergic neurons in developing rats. Recent studies have revealed that an adenosine agonist, NECA, will antagonize SMB produced by the dopamine agonist, L-DOPA, after 6-OHDA treatment. Therefore, the ability of relatively specific adenosine agonists to block L-DOPA-induced behaviors as well as those produced by D-1 and D-2 dopamine receptor agonists will be investigated. We will explore if antagonism of adenosine receptors will produce SMB in neonatally-6-OHDA-treated rats or increase the effectiveness of dopamine agonists to induce this and other behaviors. In vitro experiments are proposed in 6-OHDA-lesioned rats to measure striatal adenosine receptor characteristics and the ability of adenosine agonists to interact with D-1 dopamine agonist activation of striatal adenylate cyclase. Possible involvement of GTP in the supersensitivity of D-1 dopamine receptors in neo-natally-6-OHDA-treated rats will also be examined. Electrophysiological studies are planned to characterize interactions of adenosine and a selected dopamine agonist at the cellular level in striatum of control and lesioned animals. This multidisciplinary evaluation of dopamine-purine interactions should allow us: (1) to assess if HGPRT is contained in dopaminergic neurons and if purine compounds influence development of dopaminergic neurons; (2) to determine if 6-OHDA treatment alters adenosine receptors, their function, or action of GTP on adenylate cyclase activity; and (3) to define how alterations in an adenosine receptor subtype will influence specific dopamine receptor subtype mediated responses. Data collected in these three areas will increase our basic understanding of purine-dopamine interactions and could provide new strategies for treating SMB and other symptoms in LNS.

Lesch-Nyhan综合征（LNS）的特征是 酶，HGPRT，运动功能障碍，智力低下，高尿酸血症， 自溶性行为（SMB）和多巴胺能神经元的丧失。 在 大鼠，用6-羟基多巴胺对多巴胺能神经元的新生儿破坏 （6-OHDA）当D-1多巴胺受体是 激活，表明新生儿6-霍达治疗是一种模型 LNS中央多巴胺缺乏。 目前的赠款探讨了如何 酶和改变的嘌呤机制可能与多巴胺能相互作用 功能。 我们计划确定HGPRT的相对量 通过测量HGPRT活性后，含多巴胺的（或其他）神经元之后 神经毒素治疗。 我们还将确定是否嘌呤化合物，哪个化合物 积聚在LN中，影响多巴胺能神经元在 发育的老鼠。 最近的研究表明，腺苷激动剂， NECA，将与多巴胺激动剂L-DOPA产生的SMB对抗 6-OHDA治疗。 因此，相对特异的腺苷的能力 激动剂阻止L-DOPA诱导的行为以及D-1产生的行为 将研究D-2多巴胺受体激动剂。 我们将探索 如果腺苷受体的拮抗作用会在 新生儿6-OHDA治疗的大鼠或增加多巴胺的有效性 激动者诱导这种行为和其他行为。 体外实验是 在6- OHDA的大鼠中提议测量纹状体腺苷受体 特征和腺苷激动剂与D-1相互作用的能力 纹状体腺苷酸环化酶的多巴胺激动剂激活。 可能的 GTP参与D-1多巴胺受体的超敏性 还将检查新的6-OHDA治疗的大鼠。 计划进行电生理研究以表征 腺苷和选定的多巴胺激动剂在纹状体中的细胞水平 控制和病变的动物。 这种多学科评估 多巴胺 - 公用相互作用应允许我们：（1）评估HGPRT是否是 含有多巴胺能神经元和嘌呤化合物的影响 多巴胺能神经元的发展； （2）确定6-OHDA是否治疗 改变腺苷受体，其功能或GTP对腺苷酸盐的作用 环化酶活性； （3）定义腺苷中的改变 受体亚型将影响特定的多巴胺受体亚型介导 回答。 在这三个领域收集的数据将增加我们的基本 理解嘌呤 - 多巴胺相互作用，可以提供新的 治疗LNS中SMB和其他症状的策略。