Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors
Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors
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DOI：
10.1016/s0028-3908(98)00208-1
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发表时间：
1999-04-01
影响因子：
4.7
通讯作者：
Kendall, DA
中科院分区：
文献类型：
--
作者：
Cheer, JF;Cadogan, AK;Kendall, DA
油酰胺(顺-9，10-十八碳烯酰胺)是一种内源性脑脂类物质，已被认为可诱导实验动物睡眠。作用机制尚不清楚，但具有内源性大麻素的许多特征，如阿南达胺，并已被证明在体外增强对5-羟色胺和GABA的反应。在本研究中，我们观察了油酰胺对5-羟色胺受体激动剂DOI(+/-)-1-(2，5-dimethoxy-4-iodophenyl)-2-aminopropane盐酸盐)引起的大鼠两种运动行为--背部肌肉收缩和湿狗抖动的影响。然后，我们研究了CB1大麻素受体在油酰胺反应中的潜在参与，以及CB1和5-HT2受体之间的相互作用机制。油酰胺和大麻素受体激动剂HU210(6aR)-trans-3-(1，1-dimethylheptyl)6a，7，10，10a-tetrahydro-1-hydroxy-6，6-dimethyl-6H-dibenzo[b，-d]吡喃-9-甲醇产生一种异构化反应，而CB拮抗剂SR141716A(N-(哌啶-1-基)-5-(4-氯苯基)-1H-吡唑-3-甲酰胺盐酸盐)可阻止这种反应。尽管油酰胺和HU210单独作用不明显，但它们能增强DOI诱导的BMC。SR141716A单独对DOI的反应没有影响，但它能阻断油酰胺或HU210引起的增强作用。油酰胺对WDS无影响，HU210使WDS略有减少。在体外，油酰胺和HU210增强了H-3-酮丝氨酸标记的大鼠大脑皮层膜上5-羟色胺与5-HT2受体的高亲和力结合。然而，这两种药物都不能改变5-羟色胺刺激的大鼠大脑皮层脑片中肌醇磷脂的水解。油酰胺在H-3-CP55940标记的大鼠脑膜上占据了CB1大麻素受体，IC50为10微米。这一数据与油酰胺在体内通过大麻素识别部位增强5-HT2受体功能的作用是一致的。这种调节的机制尚不清楚，但似乎并不涉及5-HT2受体刺激的肌醇磷脂水解酶的增强作用。(C)1999爱思唯尔科学有限公司。保留所有权利。
Oleamide (cis-9,10-octadecenoamide) is an endogenous brain lipid which has been suggested to induce sleep in experimental animals. The mechanism of action is unclear but shares many of the characteristics of endogenous cannabinoids such as anandamide and has been shown to enhance in vitro responses to 5-HT and GABA. In the present study we investigated the effects of oleamide on two motor behaviours, back muscle contractions (BMC) and wet-dog shakes (WDS) induced in rats by treatment with the 5-HT2 receptor agonist DOI ((+ / -)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride). We then examined the potential involvement of CB1 cannabinoid receptors in the responses to oleamide and the mechanism of interaction between CB1 and 5-HT2 receptors. Oleamide and the cannabinoid receptor agonist HU210 (6aR)-trans-3-(1,1-dimethylheptyl)6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol) produced a hypolocomotion which was prevented by the CB, antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1 1H-pyrazole-3-carboxamide hydrochloride). Despite having no effect alone, oleamide and HU210 potentiated BMC induced by treatment with DOI. SR141716A alone did not affect the response to DOI but it blocked the potentiations caused by oleamide or HU210. WDS were unaffected by oleamide and slightly reduced by HU210. In vitro, oleamide and HU210 enhanced the high affinity binding of 5-HT to 5-HT2 receptors on rat cerebral cortex membranes labelled with H-3-ketanserin. Neither agent, however, altered 5-HT-stimulated phosphoinositide hydrolysis in rat cerebral cortex slices. Oleamide occupied CB1 cannabinoid receptors on rat brain membranes labelled with H-3-CP55940 with an IC50 of 10 mu M. The data presented are consistent with oleamide acting via a cannabinoid recognition site to enhance 5-HT2 receptor function in vivo. The mechanism of the modulation is still unclear but it does not appear to involve a potentiation of 5-HT2 receptor-stimulated phosphoinositide hydrolysis. (C) 1999 Elsevier Science Ltd. All rights reserved.