Pierucci Massimo, Di Matteo Vincenzo, Esposito Ennio
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Chieti, Italy.
J Pharmacol Exp Ther. 2004 Apr;309(1):109-18. doi: 10.1124/jpet.103.062208. Epub 2004 Jan 13.
In vivo electrophysiological techniques were used to study the effect of nicotine on the basal activity of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) of chloral hydrate-anesthetized rats. Acute i.v. injections of nicotine (25-400 microg/kg) caused a dose-dependent increase of the firing rate and the bursting activity of DA neurons both in the SNc and the VTA. Repeated daily injection of nicotine (1 mg/kg i.p.) for 10 consecutive days did not cause any significant change in the basal activity of DA neurons in the SNc and the VTA. Acute challenge with nicotine (25-400 microg/kg i.v.) in animals treated repeatedly with this drug caused a dose-related excitation of DA neurons in both areas. To test the hypothesis that stimulation of 5-hydroxytryptamine (5-HT, serotonin)(2C) receptors could affect nicotine-induced stimulation of DA neuronal activity, the selective 5-HT(2C) receptor agonist RO 60-0175 was used. Pretreatment with 100 microg/kg i.v. (S)-2-(chloro-5-fluoro-indo-l-yl)-l-methylethylamine 1:1 C(4)H(4)O(4) (RO 60-0175) prevented the enhancement in DA neuronal firing rate elicited by acute nicotine (25-400 microg/kg i.v.) in the SNc of both drug naive and chronically treated rats but was devoid of any significant effect in the VTA. Moreover, the dose of 300 microg/kg i.v. RO 60-0175 significantly reduced the stimulatory effect of VTA DA neurons induced by acute challenge with nicotine (25-400 microg/kg i.v.) both in drug naive and chronically treated rats. It is concluded that selective activation of 5-HT(2C) receptors can block the stimulatory action of nicotine on midbrain DA neuronal activity.
采用体内电生理技术，研究尼古丁对水合氯醛麻醉大鼠黑质致密部（SNc）和腹侧被盖区（VTA）中含多巴胺（DA）神经元基础活性的影响。急性静脉注射尼古丁（25 - 400微克/千克）可使SNc和VTA中DA神经元的放电频率和爆发活动呈剂量依赖性增加。连续10天每日重复腹腔注射尼古丁（1毫克/千克），未引起SNc和VTA中DA神经元基础活性的任何显著变化。在反复用该药物处理的动物中，急性注射尼古丁（25 - 400微克/千克静脉注射）可引起两个区域DA神经元的剂量相关兴奋。为了验证刺激5 - 羟色胺（5 - HT，血清素）（2C）受体是否会影响尼古丁诱导的DA神经元活动刺激，使用了选择性5 - HT（2C）受体激动剂RO 60 - 0175。静脉注射100微克/千克（S）-2 - （氯 - 5 - 氟 - 吲哚 - 1 - 基）-1 - 甲基乙胺1:1 C₄H₄O₄（RO 60 - 0175）预处理，可防止急性尼古丁（25 - 400微克/千克静脉注射）在未用药和长期处理的大鼠SNc中引起的DA神经元放电频率增强，但对VTA无任何显著影响。此外，静脉注射300微克/千克的RO 60 - 0175可显著降低急性注射尼古丁（25 - 400微克/千克静脉注射）在未用药和长期处理的大鼠中诱导的VTA DA神经元的刺激作用。结论是，5 - HT（2C）受体的选择性激活可阻断尼古丁对中脑DA神经元活动的刺激作用。
