Kittner Holger, Franke Heike, Harsch Julia I, El-Ashmawy Ibrahim M, Seidel Bertholt, Krügel Ute, Illes Peter
Rudolf-Boehm-Institute of Pharmacology and Toxicology, and Children's Hospital, University of Leipzig, D-04107 Leipzig, Germany.
Eur J Neurosci. 2006 Oct;24(7):2049-56. doi: 10.1111/j.1460-9568.2006.05071.x.
The present study was aimed to clarify the role of purinergic signalling in the regulation of ingestion behaviour. The ATP/ADP analogues 2-methylthioATP (2-MeSATP) and adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS) increased the food intake after intracerebroventricular infusion in 18-h food-deprived rats. This effect was abolished by pretreatment with the non-selective P2X/P2Y receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) or the selective P2Y1 receptor antagonist MRS 2179, respectively. The stimulation of food intake mediated by ADPbetaS was also blocked by pretreatment with the nitric oxide synthase (NOS) inhibitor Nw-nitro-L-arginine methylester (L-NAME), as well as with the inhibitor of the soluble guanylyl cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), suggesting that the orexigenic effect seems to be closely related with the ensuing formation of nitric oxide. The immunohistochemical staining indicating a co-localization of P2Y1 receptor- and nNOS-immunoreactivities in a population of neurons in the ventromedial hypothalamic nucleus (VMH) agrees with this assumption. Further experiments with the direct local application of these compounds into the VMH and lateral hypothalamic nucleus (LH) show that the stimulation of P2Y1 receptors in these functionally antagonistic brain regions exerts an increased food intake. Hence, different signal transduction mechanisms may operate in the VMH and LH. Our assumption is supported by distinct effects of the NOS inhibitor L-NAME in these two hypothalamic nuclei. The present data suggest that ATP/ADP, acting as extracellular signal molecules in the rat brain, are involved in the regulation of food intake, possibly depending on P2Y1-receptor-mediated nitric oxide production.
本研究旨在阐明嘌呤能信号在摄食行为调节中的作用。在对禁食18小时的大鼠进行脑室内注射后，ATP/ADP类似物2-甲硫基ATP（2-MeSATP）和腺苷5'-O-(2-硫代二磷酸)（ADPβS）增加了食物摄入量。分别用非选择性P2X/P2Y受体拮抗剂吡哆醛磷酸-6-偶氮苯基-2',4'-二磺酸（PPADS）或选择性P2Y1受体拮抗剂MRS 2179预处理可消除这种作用。由ADPβS介导的食物摄入刺激也被一氧化氮合酶（NOS）抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME）以及可溶性鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ）预处理所阻断，这表明促食欲作用似乎与随后一氧化氮的形成密切相关。免疫组织化学染色显示，腹内侧下丘脑核（VMH）中一群神经元内P2Y1受体免疫反应性和nNOS免疫反应性共定位，这与该假设相符。将这些化合物直接局部应用于VMH和外侧下丘脑核（LH）的进一步实验表明，在这些功能上相互拮抗的脑区中刺激P2Y1受体会增加食物摄入量。因此，不同的信号转导机制可能在VMH和LH中起作用。我们的假设得到了NOS抑制剂L-NAME在这两个下丘脑核中的不同作用的支持。目前的数据表明，ATP/ADP作为大鼠脑中的细胞外信号分子，参与了食物摄入的调节，可能依赖于P2Y1受体介导的一氧化氮产生。
