Renoir Thibault, Argyropoulos Andrew, Chevarin Caroline, Lanfumey Laurence, Hannan Anthony J
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia.
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia; Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Australia.
Pharmacol Biochem Behav. 2014 Dec;127:15-20. doi: 10.1016/j.pbb.2014.10.004. Epub 2014 Oct 12.
Using the R6/1 transgenic mouse model of Huntington's disease (HD), we have recently shown that acute administration with the dopamine-norepinephrine reuptake inhibitor bupropion was able to rescue depressive-like behaviours in female HD mice at 12weeks of age.
In this present study, we aimed to further investigate the dopamine system as well as specifically measure dopamine transporter (DAT) and D1 receptor function in female versus male R6/1 HD mice at a very early stage of the disease.
We assessed the effects of acute administration of bupropion and the dopamine D1 receptor agonist SKF-8129 on spontaneous locomotor activity in 8-week-old HD and wild-type (WT) mice. We also measured dopamine levels in striatum via high performance liquid chromatography (HPLC).
We found that female (but not male) HD mice were hyposensitive to bupropion when compared to WT littermates. However, both female and male HD mice were less sensitive to SKF-81297 locomotor effects. We also found that striatal dopamine levels and dopamine turnover were reduced in HD animals, regardless of sex.
Our present findings suggest that whereas only female HD mice exhibit an impaired response to bupropion, dopamine D1 receptor function is altered in both female and male HD animals. These data are the first in vivo evidence of impaired dopamine D1 receptor-dependent function in pre-motor symptomatic HD mice suggesting that this is a candidate target for early therapeutic interventions.
利用亨廷顿舞蹈病（HD）的R6/1转基因小鼠模型，我们最近发现，急性给予多巴胺-去甲肾上腺素再摄取抑制剂安非他酮能够挽救12周龄雌性HD小鼠的抑郁样行为。
在本研究中，我们旨在进一步研究多巴胺系统，并在疾病的极早期阶段，特别测量雌性和雄性R6/1 HD小鼠的多巴胺转运体（DAT）和D1受体功能。
我们评估了急性给予安非他酮和多巴胺D1受体激动剂SKF-8129对8周龄HD和野生型（WT）小鼠自发运动活动的影响。我们还通过高效液相色谱法（HPLC）测量纹状体中的多巴胺水平。
我们发现，与野生型同窝小鼠相比，雌性（而非雄性）HD小鼠对安非他酮反应迟钝。然而，雌性和雄性HD小鼠对SKF-8129的运动效应均不敏感。我们还发现，无论性别，HD动物纹状体中的多巴胺水平和多巴胺周转率均降低。
我们目前的研究结果表明，虽然只有雌性HD小鼠对安非他酮的反应受损，但雌性和雄性HD动物的多巴胺D1受体功能均发生改变。这些数据是运动前有症状的HD小鼠中多巴胺D1受体依赖性功能受损的首个体内证据，表明这是早期治疗干预的候选靶点。
