Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
Neurobiol Dis. 2020 Sep;143:105017. doi: 10.1016/j.nbd.2020.105017. Epub 2020 Jul 14.
Dopamine receptors interact with other receptors to form heterooligomers. One such complex, the D1-D2 heteromer, demonstrated in cultured striatal neurons and rat striatum has been linked to drug addiction, Parkinson's disease, schizophrenia, depression and anhedonia.
D1-D2 heteromer expression was evaluated using in situ proximity ligation assay, in parallel with cellular colocalization of D1 and D2 mRNA using in situ hybridization in 19 different key rat brain regions. Expression in higher species and changes in rat striatum after repeated cocaine administration were evaluated.
Differences in D1-D2 heteromer expression in striatal subregions are documented in higher species with nonhuman primate and human demonstrating higher density of heteromer-expressing neurons compared to rodents. All species had higher density of D1-D2 neurons in nucleus accumbens compared to dorsal striatum. Multiple other brain regions are identified where D1-D2 heteromer is expressed, prominently in cerebral cortical subregions including piriform, medial prefrontal, orbitofrontal and others; subcortical regions such as claustrum, amygdala and lateral habenula. Three categories of regions are identified: D1-D2 heteromer expressed despite little to no observed D1/D2 mRNA colocalization, likely representing heteromer on neuronal projections from other brain regions; D1-D2 heteromer originating locally with the density of neurons expressing heteromer matching neurons with colocalized D1/D2 mRNA; regions with both a local origin and targeted inputs projecting from other regions. Repeated cocaine administration significantly increased density of neurons expressing D1-D2 heteromer and D1/D2 mRNA colocalization in rat striatum, with changes in both direct and indirect pathway neurons.
The dopamine D1-D2 heteromer is expressed in key brain cortical and subcortical regions of all species examined. Species differences in striatum revealed greater abundance in human>nonhuman-primate>rat>mouse, suggesting an evolutionary biologic role for the D1-D2 heteromer in higher CNS function. Its upregulation in rat striatum following cocaine points to regulatory significance with possible relevance for clinical disorders such as drug addiction. The dopamine D1-D2 receptor heteromer may represent a potential target for neuropsychiatric and neurodegenerative disorders, given its distribution in highly relevant brain regions.
多巴胺受体与其他受体相互作用形成异源寡聚体。在培养的纹状体神经元和大鼠纹状体中发现的一种这样的复合物，即 D1-D2 异源二聚体，与药物成瘾、帕金森病、精神分裂症、抑郁症和快感缺失有关。
使用原位邻近连接分析评估 D1-D2 异源二聚体的表达，同时使用原位杂交平行评估 D1 和 D2 mRNA 在 19 个不同关键大鼠脑区的细胞共定位。评估了在更高物种中的表达以及在重复可卡因给药后大鼠纹状体中的变化。
在更高物种中记录了纹状体亚区中 D1-D2 异源二聚体表达的差异，与啮齿动物相比，非人类灵长类动物和人类表现出更高密度的异源二聚体表达神经元。与背侧纹状体相比，所有物种的伏隔核中 D1-D2 神经元的密度更高。还确定了多个其他脑区表达 D1-D2 异源二聚体，特别是在大脑皮质亚区，包括梨状皮层、内侧前额叶皮质、眶额皮质等；皮质下区域，如屏状核、杏仁核和外侧缰核。鉴定出三类区域：尽管观察到很少或没有观察到 D1/D2 mRNA 共定位，但表达 D1-D2 异源二聚体，可能代表来自其他脑区的神经元投射上的异源二聚体；起源于局部的 D1-D2 异源二聚体，与共表达 D1/D2 mRNA 的神经元的神经元密度相匹配；具有局部起源和来自其他区域的靶向输入的区域。重复可卡因给药显著增加了大鼠纹状体中表达 D1-D2 异源二聚体和 D1/D2 mRNA 共定位的神经元密度，直接和间接通路神经元均发生变化。
多巴胺 D1-D2 异源二聚体在所有检查的物种的关键大脑皮质和皮质下区域表达。在纹状体中观察到的物种差异表明，人类>非人类灵长类动物>大鼠>小鼠中的丰度更高，表明 D1-D2 异源二聚体在高等中枢神经系统功能中的进化生物学作用。可卡因给药后大鼠纹状体中 D1-D2 异源二聚体的上调表明其具有调节意义，可能与药物成瘾等临床疾病有关。鉴于其在高度相关的脑区中的分布，多巴胺 D1-D2 受体异源二聚体可能成为神经精神和神经退行性疾病的潜在靶点。
