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（由申请人提供）：D2 多巴胺受体（D2R）在所有类型的药物滥用者中均显着下调。然而，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 丧失的分子机制仍未解决。多巴胺受体介导的信号传导受到许多过程的调节。一种方法是通过内吞作用，受体在激活后从细胞表面去除。内吞作用后，不同的多巴胺受体进行不同的分类：D1R 被回收，而 D2R 被降解。我们已经鉴定出一种蛋白质 GASP1，它负责靶向 D2R 进行内吞作用后的降解。我们接着提出，在高多巴胺张力条件下，由于 D2R 的下调，D1R-Gs 信号传导与 D2R-Gi 信号传导在对药物滥用至关重要的电路中的平衡被破坏，从而促进可塑性和行为的变化。为了支持这一假设，GASP1 的基因破坏可以防止可卡因诱导的 D2R 下调，并减弱小鼠对可卡因运动敏感性的发展。在这里，我们将研究改变 D2R 和 D1R 信号传导的平衡如何影响对可卡因的运动（目标 1）和奖励（目标 2）效应的敏感性。然后，我们将评估伏核、腹侧被盖区、基底外侧杏仁核或内侧前额叶皮层选定神经元中多巴胺受体信号平衡的变化是否必要或足以影响这些行为（目标 3）。我们将部分地利用我们已经产生的新型转基因工具来实现这一目标，包括条件和非条件 GASP1 敲除 (KO) 小鼠，以及表达不结合 GASP1 的 D2R 的敲入小鼠。我们还将使用市售且具有治疗意义的多巴胺能配体来探讨 D2R 下调在改变行为中的作用问题。尽管这些配体的“药理学”已经研究了一段时间，但我们方法的创新在于我们不仅检查经典的药理学特性，例如配体亲和力和选择性，而且还检查这些配体对内吞和内吞后受体运输的影响。