Maina Francis K, Mathews Tiffany A
Department of Chemistry, Wayne State University, Detroit, MI, 48202.
ACS Chem Neurosci. 2010 Mar 12;1(6):450-462. doi: 10.1021/cn100003u.
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 EC(50) 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 muM 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.
多巴胺D2和D3自身受体位于突触前终末，已知可控制多巴胺的释放和合成。多巴胺D3受体在哺乳动物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特别受关注，因为它们与滥用药物的奖赏特性有关。我们使用背景扣除快速扫描循环伏安法，研究了多巴胺D2和D3激动剂对小鼠尾状核 - 壳核以及伏隔核核心和壳层中电刺激的多巴胺释放和摄取速率的影响。多巴胺D2激动剂（-）-喹吡罗盐酸盐和5,6,7,8 - 四氢 - 6 - （2 - 丙烯 - 1 - 基）-4H - 噻唑并[4,5 - d]氮杂 - 2 - 胺二盐酸盐（B - HT 920）基于其半数有效浓度（EC50）和效能，对尾状核 - 壳核以及伏隔核（核心和壳层）具有相同的多巴胺释放抑制作用。这表明多巴胺D2自身受体功能在所研究的所有三个纹状体区域中具有可比性。多巴胺D3激动剂（4aR，10bR）-3,4a,4,10b - 四氢 - 4 - 丙基 - 2H，5H - [1]苯并吡喃并[4,3 - b] - 1,4 - 恶嗪 - 9 - 醇盐酸盐（（+）-PD 128907）和（±）-7 - 羟基 - 2 - 二丙基氨基四氢萘氢溴酸盐（7 - OH - DPAT）对伏隔核壳层中多巴胺释放抑制的作用比对尾状核 - 壳核的作用显著更大。本研究证实，多巴胺D3自身受体功能在伏隔核壳层中最强，其次是伏隔核核心，尾状核 - 壳核中最弱。多巴胺D2和D3激动剂均未影响伏隔核中的摄取速率，但浓度大于0.3μM时会降低尾状核 - 壳核中的摄取速率。为了验证我们评估多巴胺D2和D3自身受体的方法，使用舒必利（D2拮抗剂）和萘法朵利（D3拮抗剂）将多巴胺激动剂的作用逆转至接近激动剂前多巴胺释放浓度的100％。最后，这些结果证明了一种功能性伏安测定法，该方法通过利用纹状体内独特的受体密度，将多巴胺D2样激动剂表征为D2或D3偏好激动剂。
