Gago Belén, Fuxe Kjell, Agnati Luigi, Peñafiel Antonio, De La Calle Adelaida, Rivera Alicia
Department of Cell Biology, School of Science, University of Málaga, 29071 Málaga, Spain.
J Comp Neurol. 2007 May 20;502(3):358-66. doi: 10.1002/cne.21327.
The dopaminergic and opioid peptide systems interact in many nuclei of the brain. In the striatum, dopamine/opioid peptide interactions modulate locomotor and motivated behaviors as well as reward, motivational, and tolerance processes in opiate dependence. Dopamine D(4) receptors (D(4) R) and mu-opioid receptors (MOR) are highly concentrated in the striosomes (islands) of the striatum, suggesting the existence of receptor-receptor interactions between them. In the present work we studied the role of D(4) R in modulating MOR expression in the islands by using immunohistochemistry and image analysis. The activation of D(4) R by the agonist PD168,077 (1 mg/kg) decreased MOR immunoreactivity (IR) in the striosomes 6 hours after drug treatment. MOR IR levels had recovered 12 hours later. Treatment with a D(4) R antagonist (L745,870, 1mg/kg) blocked downregulation of MOR IR, showing that the D(4) R agonist effects observed were specific. Furthermore, treatment with the D(2)/D(3) receptor agonist quinpirol (1 mg/kg) and D(2)/D(3) receptor antagonist raclopride (1 mg/kg) had no effect in MOR IR, suggesting that D(4) R is the only D2-like receptor producing an MOR downregulation in the islands. The decreases of MOR IR in the striosomes suggest that D(4) R activation may reduce MOR signaling. Increasing evidence has demonstrated that the islands in the striatum play a critical role in habit acquisition during drug addiction. D(4) R/MOR interactions could be crucial in such processes.
多巴胺能系统和阿片肽系统在大脑的许多核团中相互作用。在纹状体中，多巴胺/阿片肽相互作用调节运动和动机行为以及阿片类药物依赖中的奖赏、动机和耐受过程。多巴胺D(4)受体（D(4)R）和μ-阿片受体（MOR）高度集中在纹状体的纹状小体（岛）中，提示它们之间存在受体-受体相互作用。在本研究中，我们通过免疫组织化学和图像分析研究了D(4)R在调节纹状小体中MOR表达方面的作用。激动剂PD168,077（1mg/kg）激活D(4)R后，在药物处理6小时后降低了纹状小体中的MOR免疫反应性（IR）。12小时后MOR IR水平恢复。用D(4)R拮抗剂（L745,870，1mg/kg）处理可阻断MOR IR的下调，表明观察到的D(4)R激动剂效应是特异性的。此外，用D(2)/D(3)受体激动剂喹吡罗（1mg/kg）和D(2)/D(3)受体拮抗剂雷氯必利（1mg/kg）处理对MOR IR没有影响，提示D(4)R是唯一在纹状小体中产生MOR下调的D2样受体。纹状小体中MOR IR的降低表明D(4)R激活可能会减少MOR信号传导。越来越多的证据表明，纹状体中的纹状小体在药物成瘾过程中的习惯形成中起关键作用。D(4)R/MOR相互作用在此类过程中可能至关重要。
