Villégier Anne-Sophie, Drouin Candice, Bizot Jean-Charles, Marien Marc, Glowinski Jacques, Colpaërt Francis, Tassin Jean-Pol
Inserm U. 114, Collège de France, 75231 Paris, France.
Synapse. 2003 Dec 15;50(4):277-84. doi: 10.1002/syn.10267.
Recent experiments have shown that mice lacking the alpha1b-adrenergic receptor (alpha1b-AR KO) are less responsive to the locomotor hyperactivity induced by psychostimulants, such as D-amphetamine or cocaine, than their wild-type littermates (WT). These findings suggested that psychostimulants induce locomotor hyperactivity not only because they increase dopamine (DA) transmission, but also because they release norepinephrine (NE). To test whether NE release could increase DA-mediated locomotor hyperactivity, rats were treated with GBR 12783 (10 mg/kg), a specific inhibitor of the DA transporter, and NE release was enhanced with dexefaroxan (0.63-10 mg/kg), a potent and specific antagonist at alpha2-adrenergic receptors. Dexefaroxan increased the GBR 12783-mediated locomotor response by almost 8-fold. The role of alpha1b-ARs in this effect was then verified in alpha1b-AR KO mice: whereas dexefaroxan (1 mg/kg) doubled locomotor hyperactivity induced by GBR 12783 (14 mg/kg) in WT mice, it decreased it by 43% in alpha1b-AR KO mice. Finally, to test whether this latter inhibition was related to the occupation of alpha2-adrenergic autoreceptors or of alpha2-ARs not located on noradrenergic neurons, effects of dexefaroxan on locomotor hyperactivity induced by D-amphetamine (0.75 mg/kg) were monitored in rats depleted in ascending noradrenergic neurons. In these animals dexefaroxan inhibited by 25-70% D-amphetamine-induced locomotor hyperactivity. These data indicate not only that the stimulation of alpha1b-ARs increases DA-mediated locomotor response, but also suggest a significant implication of postsynaptic alpha2-ARs. Involvement of these adrenergic receptor mechanisms may be exploited in the therapy of Parkinson's disease.
最近的实验表明，缺乏α1b - 肾上腺素能受体的小鼠（α1b - AR基因敲除小鼠）比其野生型同窝小鼠（WT）对精神兴奋剂（如D - 苯丙胺或可卡因）诱导的运动活动亢进反应性更低。这些发现表明，精神兴奋剂诱导运动活动亢进不仅是因为它们增加了多巴胺（DA）传递，还因为它们释放了去甲肾上腺素（NE）。为了测试NE释放是否能增加DA介导的运动活动亢进，给大鼠注射GBR 12783（10毫克/千克），一种DA转运体的特异性抑制剂，并使用右苯丙胺（0.63 - 10毫克/千克）增强NE释放，右苯丙胺是α2 - 肾上腺素能受体的强效特异性拮抗剂。右苯丙胺使GBR 12783介导的运动反应增加了近8倍。然后在α1b - AR基因敲除小鼠中验证了α1b - ARs在这种效应中的作用：虽然右苯丙胺（1毫克/千克）使GBR 12783（14毫克/千克）在WT小鼠中诱导的运动活动亢进增加了一倍，但在α1b - AR基因敲除小鼠中却使其降低了43%。最后，为了测试后一种抑制是否与α2 - 肾上腺素能自身受体的占据或与位于去甲肾上腺素能神经元上的α2 - ARs无关，在去甲肾上腺素能神经元上行通路耗竭的大鼠中监测右苯丙胺对D - 苯丙胺（0.75毫克/千克）诱导的运动活动亢进的影响。在这些动物中，右苯丙胺抑制D - 苯丙胺诱导的运动活动亢进25% - 70%。这些数据不仅表明α1b - ARs的刺激增加了DA介导的运动反应，还表明突触后α2 - ARs有重要作用。这些肾上腺素能受体机制的参与可能在帕金森病的治疗中得到应用。
