Dopamine receptor trafficking in drug sensitization and behavioral flexibility

多巴胺受体贩运对药物致敏和行为灵活性的影响

• 批准号: 9633987
• 负责人: JENNIFER L WHISTLER
• 金额: $ 29.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9633987
• 关键词: Dopamine; receptor; trafficking; drug; sensitization

 DESCRIPTION (provided by applicant): D2 dopamine receptors (D2R) are significantly downregulated in drug abusers of all types. However, both the functional consequences of D2R downregulation for drug abuse, and the molecular mechanisms that mediate drug-induced loss of D2R in vivo remain unresolved. Dopamine receptor-mediated signaling is regulated by numerous processes. One way is by endocytosis, whereby receptors are removed from the cell surface after activation. Following endocytosis, distinct dopamine receptors are sorted differentially: the D1Rs are recycled, while the D2Rs, are degraded. We have identified a protein, GASP1, that is responsible for the targeting of the D2R for degradation after endocytosis. We went on to propose that the balance of D1R-Gs signaling versus D2R-Gi signaling in circuits important to drug abuse becomes disrupted due to downregulation of D2R under conditions of high dopamine tone, and thereby promotes changes in plasticity and behavior. In support of this hypothesis, genetic disruption of GASP1, prevents cocaine induced downregulation of D2Rs and attenuates the development of locomotor sensitization to cocaine in mice. Here, we will examine how altering the balance of D2R and D1R signaling impacts sensitivity to both the locomotor (Aim 1) and rewarding (Aim 2) effects of cocaine. We will then assess whether changes in the balance of dopamine receptor signaling in selected neurons of the nucleus accumbens, ventral tegmental area, basolateral amygdala, or medial pre-frontal cortex are either necessary or sufficient to affect these behaviors (Aim 3). We will accomplish this, in part, with novel transgenic tools we have generated, including conditional and non-conditional GASP1 knock out (KO) mice, and a knock-in mouse expressing a D2R that does not bind GASP1. We will also approach the question of the role of D2R downregulation in altering behavior using commercially available, and therapeutically important, dopaminergic ligands. Although the "pharmacology" of these ligands have been studied for some time, the innovation in our approach lies in our examination of not only classical pharmacological properties, such as ligand affinity and selectivity, but also the effects of these ligands on both endocytic and post-endocytic receptor trafficking.

 描述（由适用提供）：D2多巴胺受体（D2R）在所有类型的药物中都显着下调。但是，D2R下调对药物滥用的功能后果以及介导药物诱导的体内D2R损失的分子机制尚未解决。多巴胺受体介导的信号传导受许多过程调节。一种方法是通过内吞作用，激活后将受体从细胞表面移除。内吞作用后，对不同的多巴胺受体进行了不同的分类：D1R被回收，而D2RS则降解。我们已经鉴定出一种蛋白质GASP1，该蛋白质是靶向D2R在内吞作用后降解的靶向。我们继续提出，由于高多巴胺张力的条件下D2R的下调，D1R-GS信号传导与D2R-GI信号的平衡被破坏了，从而损害了可塑性和行为的变化。为了支持这一假设，GASP1的遗传破坏阻止了可卡因诱导的D2RS下调，并减轻了小鼠对可卡因的运动敏感性的发展。在这里，我们将研究如何改变D2R和D1R信号的平衡影响可卡因对运动的敏感性（AIM 1）和奖励（AIM 2）效应。然后，我们将评估在核伏隔元，腹侧对接区域，基底外侧杏仁核或内侧前额外皮层中多巴胺受体信号传导平衡的变化是必要的还是足以影响这些行为的（AIM 3）。我们将通过我们生成的新型转基因工具（包括条件和非条件GASP1敲除（KO）小鼠）以及一种表达不结合GASP1的D2R的敲入小鼠来完成这一目标。我们还将解决D2R下调在更改行为中使用市售和治疗重要的多巴胺能配体的作用的问题。尽管已经对这些配体的“药理学”进行了一段时间的研究，但我们方法的创新不仅在于我们不仅检查了经典的药理学特性，例如配体亲和力和选择性，而且还检查了这些配体对内吞和后心幼儿受体运输的影响。