Di Matteo Vincenzo, Pierucci Massimo, Esposito Ennio
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy.
J Neurochem. 2004 Apr;89(2):418-29. doi: 10.1111/j.1471-4159.2004.02337.x.
The effects of acute and repeated nicotine administration on the extracellular levels of dopamine (DA) in the corpus striatum and the nucleus accumbens were studied in conscious, freely moving rats by in vivo microdialysis. Acute intraperitoneal (i.p.) injection of nicotine (1 mg/kg) increased DA outflow both in the corpus striatum and the nucleus accumbens. Repeated daily injection of nicotine (1 mg/kg, i.p.) for 10 consecutive days caused a significant increase in basal DA outflow both in the corpus striatum and the nucleus accumbens. Acute challenge with nicotine (1 mg/kg, i.p.) in animals treated repeatedly with this drug enhanced DA extracellular levels in both brain areas. However, the effect of nicotine was potentiated in the nucleus accumbens, but not in the corpus striatum. To test the hypothesis that stimulation of 5-HT (5-hydroxytryptamine, serotonin)(2C) receptors could affect nicotine-induced DA release, the selective 5-HT(2C) receptor agonist RO 60-0175 was used. Pretreatment with RO 60-0175 (1 and 3 mg/kg, i.p.) dose-dependently prevented the enhancement in DA release elicited by acute nicotine in the corpus striatum, but was devoid of any significant effect in the nucleus accumbens. RO 60-0175 (1 and 3 mg/kg, i.p.) dose-dependently reduced the stimulatory effect on striatal and accumbal DA release induced by an acute challenge with nicotine (1 mg/kg, i.p.) in rats treated repeatedly with this alkaloid. However, only the effect of 3 mg/kg RO 60-0175 reached statistical significance. The inhibitory effect of RO 60-0175 on DA release induced by nicotine in the corpus striatum and the nucleus accumbens was completely prevented by SB 242084 (0.5 mg/kg, i.p.) and SB 243213 (0.5 mg/kg, i.p.), two selective antagonists of 5-HT(2C) receptors. It is concluded that selective activation of 5-HT(2C) receptors can block the stimulatory action of nicotine on central DA function, an effect that might be relevant for the reported antiaddictive properties of RO 60-0175.
通过体内微透析技术，在清醒、自由活动的大鼠中研究了急性和重复给予尼古丁对纹状体和伏隔核细胞外多巴胺（DA）水平的影响。急性腹腔注射尼古丁（1mg/kg）可使纹状体和伏隔核中的DA流出量增加。连续10天每天重复腹腔注射尼古丁（1mg/kg）可使纹状体和伏隔核中的基础DA流出量显著增加。用该药物反复处理的动物经尼古丁（1mg/kg，腹腔注射）急性激发后，两个脑区的DA细胞外水平均升高。然而，尼古丁在伏隔核中的作用增强，但在纹状体中未增强。为了检验刺激5-羟色胺（5-HT，5-羟色胺，血清素）（2C）受体是否会影响尼古丁诱导的DA释放这一假设，使用了选择性5-HT（2C）受体激动剂RO 60-0175。RO 60-0175（1和3mg/kg，腹腔注射）预处理可剂量依赖性地阻止急性尼古丁引起的纹状体中DA释放的增强，但对伏隔核无任何显著影响。RO 60-0175（1和3mg/kg，腹腔注射）剂量依赖性地降低了在反复用该生物碱处理的大鼠中，由尼古丁（1mg/kg，腹腔注射）急性激发所诱导的纹状体和伏隔核DA释放的刺激作用。然而，只有3mg/kg RO 60-0175的作用达到统计学显著性。5-HT（2C）受体的两种选择性拮抗剂SB 242084（0.5mg/kg，腹腔注射）和SB 243213（0.5mg/kg，腹腔注射）完全阻断了RO 60-0175对尼古丁在纹状体和伏隔核中诱导的DA释放的抑制作用。得出的结论是，5-HT（2C）受体的选择性激活可阻断尼古丁对中枢DA功能的刺激作用，这一作用可能与报道的RO 60-0175的抗成瘾特性相关。
