BIOCHEMISTRY OF NEUROTRANSMITTER RECEPTORS

在本申请中，我们建议调查的遗传控制， 多巴胺受体以及遗传变异影响 对精神药物的行为反应 多巴胺受体 测量嗅结节和纹状体使用3 H-ADTN，a 多巴胺能激动剂和3 H-螺哌利多，多巴胺受体拮抗剂， 作为放射性配体。 在11个近交系小鼠品系中， 观察到高达两倍的多巴胺受体数量。 相比之下， 可见放射性配体亲和力的差异。 ADTN标记不同的站点 而不是螺哌利多标记的那些。 螺哌利多与血清素 和多巴胺的网站在嗅结节，但主要结合到 纹状体中的多巴胺能部位 ADTN或螺哌利多的数量 纹状体中的结合位点不与 放射性配体结合位点的嗅结节，这表明， 多巴胺受体的遗传控制在大脑中独立运作， 嗅结节和纹状体。 如果这是真的， 具有相当大的潜在临床意义。 本报告中提出的研究 本申请寻求进一步表征ADTN和螺哌利多结合 在嗅结节和纹状体的位置。 这是为了 区分血清素和小鼠品系， 参与传递的每个配体结合位点， 结构基因变异，无论多巴胺受体在一个区域， 在另一区域的受体的独立遗传控制下， 基因控制多巴胺受体的机制。 述遗传数据 将被用于精神药理学研究， 氟哌啶醇 这些研究将确定是否遗传差异， 由这些多巴胺能活性药物的给药引起的行为 与多巴胺受体的遗传有关。

In this application we propose to investigate the genetic control on dopamine receptors and the way in which genetic variations influence behavioral responses to psychopharmacologic agents. Dopamine receptors are measured in the olfactory tubercle and corpus striatum using 3H-ADTN, a dopaminergic agonist, and 3H-spiroperidol, a dopamine receptor antagonist, as radioligands. Among eleven inbred mouse strains, variations in the number of dopamine receptors up to two-fold are observed. In contrast, no differences in radioligand affinity are seen. ADTN labels different sites than those labelled by spiroperidol. Spiroperidol binds to both serotonin and dopamine sites in the olfactory tubercle, but binds primarily to dopaminergic sites in the striatum. The number of ADTN or spiroperidol binding sites in the striatum does not correlate with the number of radioligand binding sites in the olfactory tubercle, suggesting that genetic controls on dopamine receptors operate independently in the olfactory tubercle and striatum. If this is true, the finding is of considerable potential clinical importance. The studies proposed in this application seek to further characterize ADTN and spiroperidol binding sites in both the olfactory tubercle and striatum. This is to differentiate serotonin from mouse strains to determine the number of genes involved in transmission of each ligand binding sites, the existence of structural gene variants, whether dopamine receptors in one region are under independent genetic control from receptors in the other region, and the mechanisms of gene control over dopamine receptors. The genetic data will then be used in psychopharmacology studies with amphetamine and haloperidol. These studies will determine if genetic differences in behaviors induced by administration of these dopaminergically-active drugs are associated with inheritance of dopamine receptors.