Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists
Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists
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DOI：
10.1007/s00213-010-1924-6
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发表时间：
2010-09-01
影响因子：
3.4
通讯作者：
Jenkins, Bruce G.
中科院分区：
文献类型：
--
作者：
Choi, Ji-Kyung;Mandeville, Joseph B.;Jenkins, Bruce G.
多巴胺D_3受体（D_3R）可能是药物滥用和帕金森病运动障碍的重要治疗靶点，但其功能通路尚不清楚，我们希望确定D_3R受体拮抗剂SB-277011和PG-01037以及D_3R偏好性激动剂7-OH-DPAT在体内是否具有D_3R选择性。我们进一步希望使用全脑成像来表征对D3 R药物的反应以识别新的D3 R回路，我们使用药理学MRI和用不同剂量的选择性D3 R拮抗剂和激动剂激发来研究大鼠的D3 R回路以检查脑血容量（CBV）的区域变化。我们比较了与D2 R/D3 R激动剂的区域激活模式，以及与先前的mRNA表达和放射自显影的研究。D3 R拮抗剂诱导的CBV阳性变化和D3 R激动剂的CBV阴性变化的大脑区域，包括延髓核，边缘下皮层，丘脑，脚间区，下丘脑和海马（最强的下托）。所有的D3 R-偏好药物表现出显着更大的反应，在脑桥核比在尾状核/壳核与D3 R的选择性一致，与D2 R激动剂所观察到的相反。在高剂量的D3 R激动剂下，功能变化在皮质层中分化，V-VI层产生正CBV变化，IV层产生负CBV变化。这些结果是不一致的差分D1 R和D3 R神经支配在这些层分别显示以前使用死后techniques.MRI提供了一种新的工具，用于测试在体内的选择性的新的D3 R多巴胺能配体的放射性标记可能无法使用。此外，功能性D3 R电路强烈涉及下丘脑和下托以及边缘纹状体。
Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry.We wished to determine if D3R antagonists SB-277011 and PG-01037 and D3R-preferring agonist 7-OH-DPAT are D3R selective in vivo. We further wished to characterize the response to D3R drugs using whole brain imaging to identify novel D3R circuitry.We investigated D3R circuitry in rats using pharmacologic MRI and challenge with selective D3R antagonists and agonist at various doses to examine regional changes in cerebral blood volume (CBV). We compared regional activation patterns with D2R/D3R agonists, as well as with prior studies of mRNA expression and autoradiography.D3R antagonists induced positive CBV changes and D3R agonist negative CBV changes in brain regions including nucleus accumbens, infralimbic cortex, thalamus, interpeduncular region, hypothalamus, and hippocampus (strongest in subiculum). All D3R-preferring drugs showed markedly greater responses in nucleus accumbens than in caudate/putamen consistent with D3R selectivity and contrary to what was observed with D2R agonists. At high doses of D3R agonist, functional changes were differentiated across cortical laminae, with layer V-VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are not inconsistent with differential D1R and D3R innervation in these layers respectively showed previously using post-mortem techniques.MRI provides a new tool for testing the in vivo selectivity of novel D3R dopaminergic ligands where radiolabels may not be available. Further, the functional D3R circuitry strongly involves hypothalamus and subiculum as well as the limbic striatum.