Navailles Sylvia, De Deurwaerdère Philippe, Spampinato Umberto
Unité Mixte de Recherche-Centre National de la Recherche Scientifique, Bordeaux Cedex, France.
Biol Psychiatry. 2006 Mar 15;59(6):568-75. doi: 10.1016/j.biopsych.2005.07.035. Epub 2005 Sep 22.
Central serotonin2C (5-HT2C) receptors are known to play a role in the mechanism of action of the antipsychotic drugs (APDs) clozapine and haloperidol. However, evidence for the involvement of the constitutive activity of 5-HT2C receptors in the dopamine (DA)ergic effects of APDs is lacking in vivo.
Using in vivo microdialysis in halothane-anesthetized rats, we assessed the ability of selective 5-HT2C compounds to modulate the release of DA induced by haloperidol and clozapine in the nucleus accumbens and striatum.
Both APDs induced a dose-dependent increase in accumbal and striatal DA extracellular levels. The effect of .01 mg/kg haloperidol was potentiated by the 5-HT2C inverse agonist SB 206553 (5 mg/kg) but unaltered by the 5-HT2C antagonists SB 243213 and SB 242084 (1 mg/kg). Conversely, the effect of 1 mg/kg clozapine, a dose able to reverse the decrease in DA outflow induced by the 5-HT2C agonist Ro 60-0175 (3 mg/kg), was unaffected by SB 206553 but blocked by SB 243213 (1 mg/kg) and SB 242084 (.3 and 1 mg/kg).
These results show that clozapine and haloperidol differentially alter the constitutive activity of 5-HT2C receptors and suggest that clozapine behaves as a 5-HT2C inverse agonist in vivo.
已知中枢5-羟色胺2C（5-HT2C）受体在抗精神病药物（APD）氯氮平和氟哌啶醇的作用机制中发挥作用。然而，体内缺乏5-HT2C受体组成性活性参与APD多巴胺（DA）能效应的证据。
我们在氟烷麻醉的大鼠中使用体内微透析技术，评估选择性5-HT2C化合物调节氟哌啶醇和氯氮平在伏隔核和纹状体中诱导的DA释放的能力。
两种APD均诱导伏隔核和纹状体DA细胞外水平呈剂量依赖性增加。0.01mg/kg氟哌啶醇的作用被5-HT2C反向激动剂SB 206553（5mg/kg）增强，但未被5-HT2C拮抗剂SB 243213和SB 242084（1mg/kg）改变。相反，1mg/kg氯氮平（一种能够逆转5-HT2C激动剂Ro 60-0175（3mg/kg）诱导的DA流出减少的剂量）的作用不受SB 206553影响，但被SB 243213（1mg/kg）和SB 242084（0.3和1mg/kg）阻断。
这些结果表明氯氮平和氟哌啶醇对5-HT2C受体的组成性活性有不同影响，并提示氯氮平在体内表现为5-HT2C反向激动剂。
