A functional fast scan cyclic voltammetry assay to characterize dopamine D2 and D3 autoreceptors in the mouse striatum.
A functional fast scan cyclic voltammetry assay to characterize dopamine D2 and D3 autoreceptors in the mouse striatum.
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DOI：
10.1021/cn100003u
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发表时间：
2010-03-12
影响因子：
5
通讯作者：
Mathews, Tiffany A.
中科院分区：
文献类型：
--
作者：
Maina, Francis K.;Mathews, Tiffany A.
关键词：
多巴胺D2和D3自受体位于突触前末端，控制多巴胺的释放和合成。多巴胺D3受体在哺乳动物大脑中的表达模式相当有限。它们在伏隔核核心和壳层的定位是特别有趣的，因为它们与滥用药物的奖励特性有关。采用背景差快速扫描循环伏安法，研究了多巴胺D2和D3激动剂对小鼠尾壳核和伏隔核核和壳电刺激多巴胺释放和摄取速率的影响。多巴胺D2激动剂(−)-quinpirole hydrochloride和5,6,7,8- tetrahydro- 6-(2-丙烯-1-yl)- 4h -噻唑[4,5-d]azepin-2-amine dihydrochloride （B-HT 920）对尾状壳核和伏隔核（核和壳）具有相同的多巴胺释放抑制作用。这表明多巴胺D2自身受体的功能在所有三个纹状体区域都是相似的。多巴胺D3激动剂(4aR,10bR)-3,4a,4,10b-四氢-4-丙基- 2h，5H-[1]苯并吡喃-[4,3-b]-1,4-恶嗪-9-醇盐酸盐（(+)- pd 128907）和（±）-7-羟基-2-二丙基氨基四溴化氢（7-OH-DPAT）对伏隔核壳的多巴胺释放抑制作用明显大于尾壳核。本研究证实，多巴胺D3自身受体的功能在伏隔核壳区最大，其次是伏隔核核心区，尾壳核区最小。多巴胺D2和D3激动剂均不影响伏隔核的摄取速率，但浓度大于0.3 μM会降低尾壳核的摄取速率。为了验证我们评估多巴胺D2和D3自身受体的方法，我们使用舒匹利（D2拮抗剂）和nafadotride （D3拮抗剂）将多巴胺激动剂的作用逆转到约100%的激动剂前多巴胺释放浓度。最后，通过利用纹状体内独特的受体密度，这些结果证明了一种功能伏安测定法，可以将多巴胺D2样激动剂表征为D2或d3偏好激动剂。
Dopamine D2 and D3 autoreceptors are located on pre-synaptic terminals and are known to control the release and synthesis of dopamine. Dopamine D3 receptors have a fairly restricted pattern of expression in the mammalian brain. Their localization in the nucleus accumbens core and shell is of particular interest because of their association with the rewarding properties of drugs of abuse. Using background subtracted fast scan cyclic voltammetry, we investigated the effects of dopamine D2 and D3 agonists on electrically stimulated dopamine release and uptake rates in the mouse caudate-putamen and nucleus accumbens core and shell. The dopamine D2 agonists (−)-quinpirole hydrochloride and 5,6,7,8-Tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (B-HT 920) had the same dopamine release inhibition effects on caudate-putamen and nucleus accumbens (core and shell) based on their EC50 and efficacies. This suggests that the dopamine D2 autoreceptor functionality is comparable in all three striatal regions investigated. The dopamine D3 agonists (4aR,10bR)-3,4a,4,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride ((+)-PD 128907) and (±)-7-Hydroxy-2-dipropylaminotetralin hydrobromide (7-OH-DPAT) had a significantly greater effect on dopamine release inhibition in the nucleus accumbens shell than in caudate-putamen. This study confirms that, the dopamine D3 autoreceptor functionality is greater in the nucleus accumbens shell followed by the nucleus accumbens core, with the caudate-putamen having the least. Neither dopamine D2 nor D3 agonists affected the uptake rates in nucleus accumbens but concentrations greater than 0.3 μM lowered the uptake rate in caudate-putamen. To validate our method of evaluating dopamine D2 and D3 autoreceptors, sulpiride (D2 antagonist) and nafadotride (D3 antagonist) were used to reverse the effects of the dopamine agonists to approximately 100% of the pre-agonist dopamine release concentration. Finally, these results demonstrate a functional voltammetric assay that characterizes dopamine D2-like agonist as either D2- or D3-preferring agonists by taking advantage of the unique receptor density within the striatum.
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