in vivo characterization of D2/D3 agonists & antagonists

描述(由申请人提供)： 多巴胺D2和D3受体在中脑边缘多巴胺能系统和伏隔核中高水平差异表达，已知这两个区域在调节滥用药物的强化特性方面具有重要作用。假设多巴胺D2和D3受体不同地参与奖赏和强化，使用选择性的D2和D3激动剂和拮抗剂将允许更准确地评估D2和D3受体在体内的作用。由于目前没有纯粹的D2或D3选择性激动剂或拮抗剂，而是现有的化合物对D2和D3具有不同程度的选择性，因此D2和D3的角色分配变得复杂。要测试的具体目标是：(1)现有的和新型的多巴胺能激动剂和拮抗剂在恒河猴和大鼠体内对D2和D3受体的选择性和活性的体内表征，(2)D2和D3作用激动剂和拮抗剂的增强特性的研究，以及(3)D2和D3激动剂和拮抗剂调节诸如可卡因等精神刺激剂维持的增强的能力的评估。综上所述，这些实验的结果将有助于更好地了解D2和D3受体在大脑奖励和强化途径中的具体作用，并为开发新的化合物以及针对药物滥用和成瘾的疗法提供有价值的信息。

DESCRIPTION (provided by applicant): The dopamine D2 and D3 receptors are differentially expressed at high levels within the mesolimbic dopaminergic system and the nucleus accumbens, areas known to be important in the regulation of the reinforcing properties of drugs of abuse. It is hypothesized that the dopamine D2 and D3 receptors are differentially involved in reward and reinforcement, and that utilization of selective D2 and D3 agonists and antagonists will allow for a more accurate assessment of the in vivo roles of the D2 and D3 receptors. Assignment of roles for D2 and D3 has been complicated by the fact that there are currently no purely D2 or D3 selective agonists or antagonists, rather existing compounds have varying degrees of selectivity for D2 and D3. The specific aims to be tested are: (1) in vivo characterization of existing and novel dopaminergic agonist and antagonist with regard to their selectivity for, and activities at the D2 and D3 receptors in rhesus monkeys and rats, (2) investigation of the reinforcing properties of D2 and D3 acting agonists and antagonists, and (3) evaluation of D2 and D3 agonists and antagonists with regard to their ability to modulate reinforcement maintained by psychostimulants such as cocaine. Taken together, the results of these experiments will allow for a better understanding of the specific roles of the D2 and D3 receptors in the reward and reinforcement pathways of the brain as well as provide valuable information towards the development of novel compounds as well as therapeutics aimed at drug abuse and addiction.