RECEPTOR RESERVE AT BRAIN DOPAMINE RECEPTORS

多巴胺(DA)激动剂通常在突触前更有效 (自身受体)而不是突触后DA受体在大脑中的位置。 对于新的非典型激动剂(例如EMD 23,448，3-PPP)， 选择性是惊人的。这个项目的长期目标是 是利用受体占有率理论的概念作为 这是理解这种差异的基础。假设是 测试表明，更大的受体储备(即更有效 受体占用和响应之间的耦合)发生在前 与其他主要是突触后功能性DA受体相比 纹状体，这解释了激动剂在 以前的遗址。本项目的主要具体目标是：1) 测定不同功能多巴胺受体储备的程度 大鼠纹状体中的受体；2)测定相对分子质量 不同经典药物(阿朴吗啡、N-阿朴吗啡)的内在药效 丙基去甲吗啡)和非典型药物(溴隐亭、培高利特、 喹比罗、西多巴、反式二氢利尿酸)DA激动剂 在存在储备的情况下，功能受体。功能剂量- 不同激动剂的反应曲线将在 并在体内部分阻断不可逆受体后 DA受体失活剂N-乙氧羰基-Z-乙氧基-1，2-二 氢喹啉(EEDQ)。使用既定的方法， 受体储备与多巴胺的相对内在效应 激动剂将从部分受体的图谱中确定 入住率与响应度。体外和体内模型的建立 突触前和突触后DA受体的功能活动将是 评估过了。体外DA激动剂介导的K+-抑制作用 纹状体脑片中~3H-DA和~(14)C-ACh的刺激释放 可作为突触前和突触后DA受体的模型 函数。酪氨酸羟化的体外实验研究 Forsklin治疗的突触体也将在体内进行检测，DA 激动剂介导逆转GBL诱导的纹状体蓄积 L-多巴和多巴胺激动剂诱导的纹状体ACh水平升高 可作为突触前和突触后DA受体的模型 函数。这些研究的结果是意料之中的 为了加深我们对大脑DA受体功能和 为新能源提供合理的理论(受体储备)依据 疾病中潜在副作用较少的治疗策略 精神分裂症等状态(例如，通过使用选择性 突触前DA激动剂降低多巴胺能功能)和 帕金森病(例如，使用低剂量多巴胺激动剂 相对内在效率，以便选择性地激活 假定为超敏感受体)。

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).