Université Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 5293, Bordeaux Cedex, France.
Int J Neuropsychopharmacol. 2013 Apr;16(3):593-606. doi: 10.1017/S1461145712000417. Epub 2012 May 3.
This study examined in naive or hemiparkinsonian rats the effect of various serotonin 2C (5-HT(2C)) receptor ligands differing in their intrinsic activity at 5-HT(2C) receptors on purposeless oral movements, a motor response integrated in the basal ganglia. Intraperitoneal administration of a non-selective [meta-chlorophenylpiperazine (m-CPP) 0.1-3 mg/kg], preferential [S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine, Ro60-0175, 0.1-3 mg/kg] or selective [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole, WAY163909, 0.3-10 mg/kg] 5-HT(2C) agonists enhanced oral bouts in naive rats. The 5-HT(2C) inverse agonists SB206553 [1-20 mg/kg; 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole] and S32006 [1-20 mg/kg; N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide], but not the 5-HT(2C) antagonist SB243213 [1-10 mg/kg; 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline], likewise dose-dependently enhanced oral movements. The effects induced by preferential 5-HT(2C) agonists and inverse agonists, but not by the cholinomimetic drug pilocarpine (5 mg/kg), were abolished by SB243213 underpinning its specificity. S32006-induced oral bouts was unaffected by the 5,7-dihydroxytryptamine lesions of 5-HT neurons. Nigrostriatal dopaminergic lesions potentiated oral effects induced by the agonists Ro60-0175 (3 mg/kg) and WAY163909 (1 mg/kg), but not by the inverse agonist SB206553 (10 mg/kg). The effect of Ro60-0175 in dopamine-lesioned rats was suppressed by SB243213. These data show that 5-HT(2C) agonists and full inverse agonists (but not neutral antagonists) perturb oral activity in rodents, paralleling studies of common antidepressant, anxiolytic and antipsychotic properties. The differential sensitivity of their actions to depletion of dopamine suggests recruitment of different contrasting neural mechanisms in the basal ganglia.
本研究在未处理或半帕金森病大鼠中，研究了不同内在活性的各种 5-羟色胺 2C（5-HT2C）受体配体对无目的口腔运动（基底神经节整合的运动反应）的影响。腹腔内给予非选择性[间氯苯哌嗪（m-CPP）0.1-3mg/kg]，优先选择[S-2-（6-氯-5-氟吲哚-1-基）-1-甲基乙胺，Ro60-0175，0.1-3mg/kg]或选择性[（7bR，10aR）-1,2,3,4,8,9,10,10a-八氢-7bH-环戊基-[b][1,4]二氮杂卓[6,7,1HI]吲哚，WAY163909，0.3-10mg/kg]5-HT2C 激动剂增强了未处理大鼠的口腔发作。5-HT2C 反向激动剂 SB206553[1-20mg/kg；5-甲基-1-（3-吡啶基羰基）-1,2,3,5-四氢吡咯并[2,3-f]吲哚]和 S32006[1-20mg/kg；N-吡啶-3-基-1,2-二氢-3H-苯并[e]吲哚-3-甲酰胺]，但不是 5-HT2C 拮抗剂 SB243213[1-10mg/kg；5-甲基-1-[[2-（2-甲基-3-吡啶基）氧基]-5-吡啶基]甲酰胺基]-6-三氟甲基吲哚]，同样剂量依赖性地增强了口腔运动。优先选择的 5-HT2C 激动剂和反向激动剂诱导的作用，但不是拟胆碱药物毛果芸香碱（5mg/kg）诱导的作用，被 SB243213 消除，证明了其特异性。S32006 诱导的口腔发作不受 5-HT 神经元 5,7-二羟基色胺损伤的影响。黑质纹状体多巴胺能损伤增强了激动剂 Ro60-0175（3mg/kg）和 WAY163909（1mg/kg）诱导的口腔作用，但不增强反向激动剂 SB206553（10mg/kg）诱导的口腔作用。Ro60-0175 在多巴胺损伤大鼠中的作用被 SB243213 抑制。这些数据表明，5-HT2C 激动剂和完全反向激动剂（而非中性拮抗剂）扰乱了啮齿动物的口腔活动，与常见的抗抑郁药、抗焦虑药和抗精神病药的研究相平行。它们的作用对多巴胺耗竭的敏感性差异表明，在基底神经节中募集了不同的对比神经机制。
