Pritchard Laurel M, Logue Aaron D, Hayes Scott, Welge Jeffrey A, Xu Ming, Zhang Jianhua, Berger S Paul, Richtand Neil M
Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, OH, USA.
Neuropsychopharmacology. 2003 Jan;28(1):100-7. doi: 10.1038/sj.npp.1300018.
The D3 dopamine receptor is expressed primarily in limbic brain areas, and appears to play an inhibitory role in rodent locomotor behavior. Evidence suggests a potential role for the D3 receptor in the pathology of neuropsychiatric disease. Progress in elucidating D3 receptor function has been hampered, however, by a lack of well-characterized, selective ligands and by conflicting information regarding the behavioral phenotype of D3 receptor knockout mice. Here, we describe studies evaluating the behavioral effects of (+/-)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and PD 128907, two D3 receptor agonists whose in vivo selectivity has been a topic of considerable controversy. We demonstrate that both compounds inhibit locomotion under novel environmental conditions in wild-type (WT) mice, but are without measurable behavioral effect under identical conditions in D3 receptor knockout mice. Additionally, we demonstrate that at low, D3 selective doses, these compounds are without behavioral effect in both WT and D3 receptor knockout mice that have acclimated to the testing environment. These findings suggest that D3 receptor stimulation inhibits novelty-stimulated locomotion, and establish conditions for the use of 7-OH-DPAT and PD 128907 as D3 receptor agonists in vivo. Potential implications of these observations are discussed.
D3多巴胺受体主要在边缘脑区表达，并且似乎在啮齿动物的运动行为中发挥抑制作用。有证据表明D3受体在神经精神疾病的病理学中具有潜在作用。然而，由于缺乏特征明确的选择性配体以及关于D3受体基因敲除小鼠行为表型的相互矛盾的信息，阐明D3受体功能的进展受到了阻碍。在此，我们描述了评估（±）-7-羟基-N，N-二正丙基-2-氨基四氢萘（7-OH-DPAT）和PD 128907这两种D3受体激动剂行为效应的研究，其体内选择性一直是相当有争议的话题。我们证明这两种化合物在野生型（WT）小鼠的新环境条件下均能抑制运动，但在D3受体基因敲除小鼠的相同条件下没有可测量的行为效应。此外，我们证明在低剂量、D3选择性剂量下，这些化合物对适应测试环境的WT和D3受体基因敲除小鼠均无行为影响。这些发现表明D3受体刺激抑制新奇刺激的运动，并为在体内使用7-OH-DPAT和PD 128907作为D3受体激动剂建立了条件。讨论了这些观察结果的潜在意义。
