RECEPTOR RESERVE AT BRAIN DOPAMINE RECEPTORS

多巴胺（DA）激动剂通常在突触前 （自身受体）比脑中突触后DA受体位点更高。 对于新的非典型激动剂（例如EMD 23，448，3-PPP）， 选择性是惊人的。 本项目的长期目标 是利用受体占有理论的概念， 理解这些差异的基础。 假设是 测试表明，更大的受体储备（即更有效的 受体占据和反应之间的偶联）发生在预 比其他的，主要是突触后功能的DA受体在大鼠 纹状体，这说明了在纹状体的激动剂的更大效力。 以前的网站 该项目的主要具体目标是：1） 确定在各种功能DA受体储备的程度 大鼠纹状体中的受体;和2）确定相对 各种经典（阿扑吗啡，N- 丙基去甲阿扑吗啡）和非典型（溴隐亭，培高利特， 喹吡罗、西拉多巴、反式-二氢麦角脲）DA激动剂. 有储备的功能性受体。 功能剂量- 将获得各种激动剂的响应曲线， 并且在用体内药物部分不可逆受体阻断后， DA受体灭活剂N-乙氧羰基-Z-乙氧基-1，2-二 氢化喹啉（EEDQ）。 使用现有方法， 受体储备和DA的相对内在功效 激动剂将从分数受体的曲线确定 占用率与响应率。 体外和体内模型 突触前和突触后DA受体的功能活性将被 评估。 在体外，DA受体激动剂介导的K+- 刺激纹状体脑片释放3 H-DA和14 C-ACh， 可用作突触前和突触后DA受体的模型 功能分别。 体外酪氨酸羟化 毛喉素处理的突触体也将在体内检查，DA 激动剂介导的GBL诱导的纹状体细胞聚集逆转 左旋多巴和多巴胺激动剂诱导的纹状体ACh水平升高将 可用作突触前和突触后DA受体的模型 功能分别。 这些研究的结果是预期的 为了进一步了解大脑DA受体的功能， 提供合理的理论（受体储备）基础， 潜在副作用较少的治疗策略 精神分裂症等状态（例如，通过利用选择性 突触前DA激动剂以降低多巴胺能功能）和 帕金森氏病（例如通过利用具有低剂量的DA激动剂） 相对的内在功效，以选择性地激活 假定的超敏感受体）。

Dopamine (DA) agonists are generally more potent at presynaptic (autoreceptor) than postsynaptic DA receptor sites in the brain. For new atypical agonists (e.g. EMD 23,448, 3-PPP) the degree of selectivity is striking. The long-term objective of this project is to utilize the concepts of receptor occupancy theory as the basis for understanding such differences. The hypothesis to be tested states that a larger receptor reserve (i.e. more efficient coupling between receptor occupation and response) occurs at pre- than other, mostly postsynaptic functional DA receptors in rat striatum, which accounts for the greater potency of agonists at the former sites. The main specific aims of this project are: 1) to determine the extent of receptor reserve at various functional DA receptors in rat striatum; and 2) to determine the relative intrinsic efficacies of various classical (apomorphine, N- propylnorapomorphine) and atypical (bromocriptine, pergolide, quinpirole, ciladopa, trans-dihydrolisuride) DA agonists at functional receptors where a reserve exists. Functional dose- response curves for the various agonists will be obtained before and after partial irreversible receptor blockade with the in vivo DA receptor inactivating agent N-ethoxycarbonyl-Z-ethoxy-1,2-di- hydroquinoline (EEDQ). Using established methods, the extent of receptor reserve and the relative intrinsic efficacies of DA agonists will be determined from plots of fractional receptor occupancy vs. response. Both in vitro and in vivo models of functional activity at pre- and postsynaptic DA receptors will be assessed. In vitro, DA agonist-mediated inhibition of K+- stimulated release of 3H-DA and 14C-ACh in striatal slices, will be utilized as models of pre- and postsynaptic DA receptor function, respectively. In vitro tyrosine hydroxylation in forskolin-treated synaptosomes will also be examined in vivo, DA agonist-mediated reversal of GBL-induced accumulation of striatal L-dopa and DA agonist-induced elevation of striatal ACh levels will be utilized as models of pre- and postsynaptic DA receptor function, respectively. The results of these studies are expected to further our understanding of brain DA receptor function and provide a rational theoretical (receptor reserve) basis for new therapeutic strategies with fewer potential side effects in disease states such as schizophrenia (e.g. by utilizing selective presynaptic DA agonists to reduce dopaminergic function) and Parkinson's disease (e.g. by utilizing DA agonists with low relative intrinsic efficacies in order to selectively activate presumed supersensitive receptors).