Collins Gregory T, Witkin Jeffrey M, Newman Amy H, Svensson Kjell A, Grundt Peter, Cao Jianjing, Woods James H
Department of Pharmacology, 1301 MSRB III, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
J Pharmacol Exp Ther. 2005 Jul;314(1):310-9. doi: 10.1124/jpet.105.085472. Epub 2005 Apr 15.
A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity. We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including PD-128,907 [(S)-(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], PD-128,908 [(R)-(-)-(4aS,10bS)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], quinelorane [(5aR-trans)-5,5a,6,7,8, 9,9a,10-octahydro-6-propylpyrido[2,3-g]quinazolin-2-amine dihydrochloride], pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [trans-(-)-(4aR)-4,4a,5,6,7,8, 8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline HCl], bromocriptine [(+)-2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl) ergotaman-3',6'-18-trione methanesulfonate], and apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol HCl] with respect to their ability to induce yawning in rats. A series of D2/D3 antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists. The antagonists L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole), haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone HCl), nafadotride (N-[(1-butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphtha-lenecarboxamide), U99194 (2,3-dihydro-5,6-dimethoxy-N,N-dipropyl-1H-inden-2-amine maleate), SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide), and PG01037 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl) were used to determine effects on dose-response curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine [(a,S)-a-(hydroxymethyl)benzeneacetic acid (1a,2b,4b,5a,7b)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine HCl), and the D3-preferring antagonists nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by PD-128,907, physostigmine [(3aS)-cis-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate hemisulfate], and N-[3-(trifluoromethyl)phenyl]piperazine HCl. The results of these experiments provide convergent evidence that dopamine D2/D3 agonist-induced yawning is a D3 agonist-mediated behavior, with subsequent inhibition of yawning being driven by competing D2 agonist activity. Thus, dopamine agonist-induced yawning may represent an in vivo method for selectively identifying D3 and D2 receptor-mediated activities.
多巴胺D3受体在行为中的具体作用尚未阐明。我们现在报告，多巴胺D2/D3激动剂在大鼠中引发剂量依赖性打哈欠行为，产生倒U形剂量反应曲线。一系列实验针对以下假设展开：打哈欠的诱导是D3受体介导的效应，而在较高剂量下观察到的打哈欠抑制是由于竞争性D2受体活性。我们比较了几种具有不同体外D3选择性的多巴胺能激动剂，包括PD - 128,907 [（S） - （+） - （4aR，10bR） - 3,4,4a，10b - 四氢 - 4 - 丙基 - 2H，5H - [1]苯并吡喃并[4,3 - b] - 1,4 - 恶嗪 - 9 - 醇盐酸盐]、PD - 128,908 [（R） - （ - ） - （4aS，10bS） - 3,4,4a，10b - 四氢 - 4 - 丙基 - 2H，5H - [1]苯并吡喃并[4,3 - b] - 1,4 - 恶嗪 - 9 - 醇盐酸盐]、喹洛雷 [（5aR - 反式） - 5,5a，6,7,8,9,9a，10 - 八氢 - 6 - 丙基吡啶并[2,3 - g]喹唑啉 - 2 - 胺二盐酸盐]、普拉克索 （N' - 丙基 - 4,5,6,7 - 四氢苯并噻唑 - 2,6 - 二胺）、7 - OH - DPAT [（+/-） - 7 - 羟基 - 2 - 二丙基氨基四氢萘氢溴酸盐]、喹吡罗 [反式 - （ - ） - （4aR） - 4,4a，5,6,7,8,8a，9 - 八氢 - 5 - 丙基 - 1H - 吡唑并[3,4 - g]喹啉盐酸盐]、溴隐亭 [（+） - 2 - 溴 - 12' - 羟基 - 2' - （1 - 甲基乙基） - 5' - （2 - 甲基丙基）麦角胺 - 3'，6' - 18 - 三酮甲磺酸盐]和阿扑吗啡 [（R） - （ - ） - 5,6,6a，7 - 四氢 - 6 - 甲基 - 4H - 二苯并[de，g]喹啉 - 10,11 - 二醇盐酸盐]在诱导大鼠打哈欠的能力方面的差异。评估了一系列对D3受体与D2受体选择性不同的D2/D3拮抗剂改变多巴胺激动剂作用的能力。拮抗剂L - 741,626 （3 - [4 - （4 - 氯苯基） - 4 - 羟基哌啶 - 1 - 基]甲基 - 1H - 吲哚）、氟哌啶醇 （4 - [4 - （4 - 氯苯基） - 4 - 羟基 - 1 - 哌啶基] - 1 - （4 - 氟苯基） - 1 - 丁酮盐酸盐）、萘法朵利 （N - [（1 - 丁基 - 2 - 吡咯烷基）甲基] - 4 - 氰基 - 1 - 甲氧基 - 2 - 萘甲酰胺）、U99194 （2,3 - 二氢 - 5,6 - 二甲氧基 - N，N - 二丙基 - 1H - 茚 - 2 - 胺马来酸盐）、SB - 277011A （反式 - N - [4 - [2 - （6 - 氰基 - 1,2,3,4 - 四氢异喹啉 - 2 - 基）乙基]环己基] - 4 - 喹啉甲酰胺）和PG01037 （N - {4 - [4 - （2,3 - 二氯苯基） - 哌嗪 - 1 - 基] - 反式 - 丁 - 2 - 烯基} - 4 - 吡啶 - 2 - 基 - 苯甲酰胺盐酸盐）用于确定对D2/D3激动剂诱导打哈欠的剂量反应曲线的影响。此外，使用一系列药理学工具，包括东莨菪碱 [（α，S） - α - （羟甲基）苯乙酸 （1α，2β，4β，5α，7β） - 9 - 甲基 - 3 - 氧杂 - 9 - 氮杂三环[3.3.1.02,4]壬 - 7 - 基酯氢溴酸盐]、米安色林 （1,2,3,4,10,14β - 六氢 - 2 - 甲基二苯并[c，f]吡嗪并[1,2 - a]氮杂卓盐酸盐）以及对D3受体具有选择性的拮抗剂萘法朵利、U99194、SB - 277011A和PG01037，来差异调节由PD - 128,907、毒扁豆碱 [（3aS） - 顺式 - 1,2,3,3a，8,8a - 六氢 - 1,3a，8 - 三甲基吡咯并[2,3 - b]吲哚 - 5 - 醇甲基氨基甲酸酯半硫酸盐]和N - [3 - （三氟甲基）苯基]哌嗪盐酸盐诱导的打哈欠，以研究胆碱能和/或5 - 羟色胺能机制对打哈欠反应的潜在贡献。这些实验结果提供了一致的证据，表明多巴胺D2/D3激动剂诱导的打哈欠是一种由D3激动剂介导的行为，随后打哈欠的抑制是由竞争性D2激动剂活性驱动的。因此，多巴胺激动剂诱导的打哈欠可能代表一种在体内选择性识别D3和D2受体介导活性的方法。
