De Deurwaerdère Philippe, Navailles Sylvia, Berg Kelly A, Clarke William P, Spampinato Umberto
Unité Mixte de Recherche Centre National de la Recherche Scientifique 5541-Université Victor Segalen Bordeaux 2, Boîte Postale 31, 33076 Bordeaux Cedex, France.
J Neurosci. 2004 Mar 31;24(13):3235-41. doi: 10.1523/JNEUROSCI.0112-04.2004.
Numerous research has pointed out that serotonin2c (5-HT2C) receptor, a subtype of 5-HT receptors belonging to the G-protein-coupled receptor superfamily, modulates the activity of mesencephalic dopamine (DA) neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. In the present study, using in vivo intracerebral microdialysis and Chinese hamster ovary (CHO) cells expressing 5-HT2C receptors to identify appropriate 5-HT2C receptor ligands, we sought to determine whether the property of 5-HT2C receptors to spontaneously activate intracellular signaling pathways in vitro (constitutive activity) participates in the tonic inhibitory control that they exert on DA release in the rat striatum and nucleus accumbens in vivo. In CHO cells, the purported antagonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole hydrochloride (SB 206553), but not 6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridin-3-yl carbamoyl] indoline (SB 242084), decreased basal inositol phosphate accumulation, thus behaving as a 5-HT2C inverse agonist. Its effect was prevented by SB 242084. In vivo, SB 206553 (1-10 mg/kg) elicited a dose-dependent and clear-cut increase in accumbal and striatal DA release compared with SB 242084 (1-10 mg/kg), and the 5-HT2C agonist S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine hydrochloride (Ro-60-0175) (0.3-3 mg/kg) inhibited DA release. Pretreatment by SB 242084 reversed the change in DA release elicited by Ro-60-0175 and SB 206553. Furthermore, SB 206553-stimulated DA release was insensitive to reduction of 5-HT neuronal function induced by the 5-HT1A agonist (+/-)-8-hydroxy-2-dipropylaminotetralin or intra-raphe injections of 5,7-dihydroxytryptamine neurotoxin. The obtained results provide the first in vivo evidence that constitutive activity of the 5-HT2C receptor tonically inhibits mesencephalic DA neurons and underscore the need for a better understanding of the pathophysiological role of constitutive receptor activity.
大量研究指出，血清素2c（5-HT2C）受体是5-HT受体的一种亚型，属于G蛋白偶联受体超家族，它可调节中脑多巴胺（DA）神经元的活性，该受体功能失调与精神分裂症、帕金森病和药物成瘾等严重疾病有关。在本研究中，我们利用体内脑内微透析技术以及表达5-HT2C受体的中国仓鼠卵巢（CHO）细胞来鉴定合适的5-HT2C受体配体，旨在确定5-HT2C受体在体外自发激活细胞内信号通路的特性（组成性活性）是否参与其在体内对大鼠纹状体和伏隔核中DA释放所施加的紧张性抑制控制。在CHO细胞中，所谓的拮抗剂盐酸5-甲基-1-（3-吡啶甲酰基）-1,2,3,5-四氢吡咯并[2,3-f]吲哚（SB 206553），而非6-氯-5-甲基-1-[6-（2-甲基吡啶-3-基氧基）吡啶-3-基甲酰基]吲哚啉（SB 2420,84）能降低基础肌醇磷酸积累，因此表现为5-HT2C反向激动剂。SB 242084可阻断其作用。在体内，与SB 242084（1 - 10 mg/kg）相比，SB 206553（1 - 10 mg/kg）能引起伏隔核和纹状体DA释放呈剂量依赖性且明显增加，而5-HT2C激动剂盐酸S-2-（6-氯-5-氟吲哚-1-基）-1-甲基乙胺（Ro-60-0175）（0.3 - 3 mg/kg）则抑制DA释放。SB 242084预处理可逆转Ro-60-0175和SB 206553引起的DA释放变化。此外，SB 206553刺激的DA释放对5-HT1A激动剂（±）-8-羟基-2-二丙基氨基四氢萘或中缝内注射5,7-二羟基色胺神经毒素诱导的5-HT神经元功能降低不敏感。所获结果首次提供了体内证据，表明5-HT2C受体的组成性活性可紧张性抑制中脑DA神经元，并强调了更好地理解组成性受体活性的病理生理作用的必要性。
