Abstract：
Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2Bird and Mecp2R168X mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2-like receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2-like receptor positive allosteric modulator, and quinpirole, a dopamine D2-like receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2-like receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2Bird/+ and Mecp2R168X/+ mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7 % CO2). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2R168X/+ and Mecp2Bird/+ mice, while also reducing respiratory rate. These results suggest that D2-like receptors could contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of D2-like receptors alone was not sufficient to evoke these effects.
摘要：
Rett综合征（RTT）是由甲基-CPG结合蛋白2（Mecp2）基因的功能丧失突变引起的自闭症谱系障碍。频繁呼吸暂停和不规则呼吸在RTT中普遍存在，也发生在该疾病的啮齿动物模型中，包括Mecp2Bird和Mecp2R168X小鼠。Sarizotan,5-羟色胺5-HT1a和多巴胺D2样受体激动剂，降低RTT小鼠模型中呼吸暂停和不规则呼吸的发生率(Abdala等人。,2014).单独靶向5HT1a受体也改善了RTT小鼠的呼吸(Levitt等人。,2013).然而,D2样受体在纠正这些呼吸紊乱方面的作用仍未得到检验.PAOPA,多巴胺D2样受体正变构调节剂，和喹吡罗,多巴胺D2样受体正位激动剂,与全身体积描记术结合使用，以评估D2样受体的激活是否足以改善雌性杂合Mecp2Bird/和Mecp2R168X/小鼠的呼吸障碍。PAOPA没有显着改变RTT小鼠的呼吸暂停发生率或不规则评分。PAOPA对高碳酸血症（7％CO2）的通气反应也没有影响。相比之下,quinpirole降低了呼吸暂停发生率和不规则评分，并改善了Mecp2R168X/和Mecp2Bird/小鼠的高碳酸血症通气反应，同时也降低了呼吸频率。这些结果表明，D2样受体可能有助于sarizotan在纠正Rett综合征的呼吸异常中的积极作用。然而,单独的D2样受体的正变构调节不足以引起这些效应.
