Devroye Céline, Cathala Adeline, Maitre Marlène, Piazza Pier Vincenzo, Abrous Djoher Nora, Revest Jean-Michel, Spampinato Umberto
Inserm, U862, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux F-33000, France.
Neuropharmacology. 2015 Feb;89:375-81. doi: 10.1016/j.neuropharm.2014.10.016.
The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.
血清素（2C）受体（5-HT（2C）R）已知可通过调节多巴胺（DA）神经元放电和终末处的DA胞吐作用来控制DA神经元功能。最近评估5-HT（2C）Rs对可卡因诱导的神经化学和行为反应影响的研究表明，5-HT2CRs还可通过控制伏隔核（NAc）中的DA传递，在突触后水平调节中脑伏隔核DA通路的活性，而与DA自身释放无关。有人提出在黑质纹状体DA系统水平也存在类似机制。在此，我们通过在自由活动的大鼠中使用体内微透析和分子方法，研究5-HT（2C）R激动剂Ro 60-0175对纹状体中可卡因诱导反应的影响，来评估这一假设。腹腔注射（i.p.）1 mg/kg Ro 60-0175对可卡因（15 mg/kg，i.p.）诱导的纹状体DA外流增加没有影响。相反，Ro 60-0175抑制了可卡因诱导的纹状体Fos免疫反应性以及DA和c-AMP调节的32 kDa Mr磷酸蛋白（DARPP-32）在苏氨酸75残基处的磷酸化。最后，选择性5-HT（2C）R拮抗剂SB 242084（0.5 mg/kg，i.p.）逆转了Ro 60-0175对可卡因诱导的DARPP-32磷酸化的抑制作用。与DARPP-32在DA神经传递中的关键作用一致，我们的结果表明，5-HT（2C）Rs能够通过特异性控制纹状体中的DA信号传导，在突触后水平调节黑质纹状体DA通路的活性。
