Zaniewska Magdalena, McCreary Andrew C, Przegaliński Edmund, Filip Malgorzata
Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, 12 Smetna, Poland.
Eur J Pharmacol. 2007 Oct 1;571(2-3):156-65. doi: 10.1016/j.ejphar.2007.05.067. Epub 2007 Jun 13.
The present study tested the hypothesis that serotonergic (5-HT) 5-HT2A or 5-HT2C receptors or their pharmacological stimulation modulated the discriminative stimulus effects of nicotine in male Wistar rats. To this end the selective 5-HT2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M100,907; 0.5-1 mg/kg, i.p.), the functional 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 0.1-1 mg/kg, s.c.), the selective 5-HT2C receptor antagonist 6-chloro-5-methyl-1-{[2-(2-methylpyrid-3-yloxy)pyrid-5-yl]carbamoyl}indoline (SB 242,084; 0.25-1 mg/kg, i.p.) and the 5-HT2C receptor agonists (S)-2-chloro-5-fluoro-indol-1-yl)-1-methylethylamine fumarate (Ro 60-0175; 0.3-1 mg/kg, s.c.) and (7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole (WAY 163,909; 0.75-1.5 mg/kg, i.p.) were used. Additionally, the effects of the selective alpha4beta2 nicotinic acetylcholine receptor subtype agonist 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-IA; 0.01 mg/kg, s.c.) were investigated. In rats trained to discriminate (-)-nicotine (0.4 mg/kg, s.c.) from saline in a two-lever, water-reinforced fixed ratio 10 task, substitutions were not observed with 5-HT2 receptor ligands (<32% nicotine-lever responding), conversely 5-IA induced a full substitution (100% nicotine-lever responding). In combination studies, fixed doses of M100,907 (0.5-1 mg/kg) or SB 242,084 (0.25-1 mg/kg) did not alter the dose-response curve of nicotine, while DOI (0.3 mg/kg), Ro 60-0175 (1 mg/kg) and WAY 163,909 (1 and 1.5 mg/kg) attenuated the discriminative stimulus effects of nicotine. The decrease in the expression of the discriminative stimulus effects of nicotine produced by DOI was blocked by M100,907 (1 mg/kg), but not by SB 242,084 (1 mg/kg), while that evoked by Ro 60-0175 or WAY 163,909 was blocked by SB 242,084 (1 mg/kg), but not by M100,907 (1 mg/kg). Further studies showed that DOI (0.3 mg/kg) and Ro 60-0175 (1 mg/kg), but not WAY 163,909 (1.5 mg/kg) blocked full substitution of 5-IA (0.01 mg/kg) for nicotine. Our pharmacological analyses indicate that tonic activation of 5-HT2A or 5-HT2C receptors is not required for subjective effects of nicotine, however these receptors appear to have inhibitory influence on nicotine cue, since pharmacological stimulation of either receptor attenuates the discriminative stimulus effects of nicotine.
血清素能（5-羟色胺，5-HT）5-HT2A或5-HT2C受体，或其药理学刺激，调节了雄性Wistar大鼠体内尼古丁的辨别刺激效应。为此，使用了选择性5-HT2A受体拮抗剂R-(+)-α-(2,3-二甲氧基苯基)-1-[2-(4-氟苯基)乙基]-4-哌啶甲醇（M100,907；0.5 - 1毫克/千克，腹腔注射）、功能性5-HT2A受体激动剂1-(2,5-二甲氧基-4-碘苯基)-2-氨基丙烷盐酸盐（DOI；0.1 - 1毫克/千克，皮下注射）、选择性5-HT2C受体拮抗剂6-氯-5-甲基-1-{[2-(2-甲基吡啶-3-基氧基)吡啶-5-基]氨基甲酰基}吲哚啉（SB 242,084；0.25 - 1毫克/千克，腹腔注射）以及5-HT2C受体激动剂富马酸(S)-2-氯-5-氟-吲哚-1-基)-1-甲基乙胺（Ro 60-0175；0.3 - 1毫克/千克，皮下注射）和(7bR, 10aR)-1,2,3,4,8,9,10,10a-八氢-7bH-环戊并[b][1,4]二氮杂环庚并[6,7,1hi]吲哚（WAY 163,909；0.75 - 1.5毫克/千克，腹腔注射）。此外，还研究了选择性α-4β-2烟碱型乙酰胆碱受体亚型激动剂5-碘-3-(2(S)-氮杂环丁烷甲氧基)吡啶（5-IA；0.01毫克/千克，皮下注射）的作用。在经过训练能在双杠杆、水强化固定比率10任务中区分(-)-尼古丁（0.4毫克/千克，皮下注射）和生理盐水的大鼠中，未观察到5-HT2受体配体引起的替代反应（尼古丁杠杆反应<32%），相反，5-IA引起了完全替代反应（100%尼古丁杠杆反应）。在联合研究中，固定剂量的M100,907（0.5 - 1毫克/千克）或SB 242,084（0.25 - 1毫克/千克）未改变尼古丁的剂量反应曲线，而DOI（0.3毫克/千克）、Ro 60-0175（1毫克/千克）和WAY 163,909（1和1.5毫克/千克）减弱了尼古丁的辨别刺激效应。DOI（0.3毫克/千克）产生的尼古丁辨别刺激效应的降低被M100,907（1毫克/千克）阻断，但未被SB 242,084（1毫克/千克）阻断，而Ro 60-0175或WAY 163,909引起的降低被SB 242,084（1毫克/千克）阻断，但未被M100,907（1毫克/千克）阻断。进一步研究表明，DOI（0.3毫克/千克）和Ro 60-0175（1毫克/千克），但不是WAY 163,909（1.5毫克/千克），阻断了5-IA（0.01毫克/千克）对尼古丁的完全替代。我们的药理学分析表明，尼古丁的主观效应不需要5-HT2A或5-HT2C受体的紧张性激活，然而这些受体似乎对尼古丁线索有抑制作用，因为对任一受体的药理学刺激都会减弱尼古丁的辨别刺激效应。
