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The novel adenosine A 2A antagonist Lu AA47070 reverses the motor and motivational effects produced by dopamine D2 receptor blockade

机译:新型腺苷A 2A拮抗剂Lu AA47070反转多巴胺D2受体封锁产生的电动机和励磁效果

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Dopamine D2 and adenosine A 2A receptors interact to regulate aspects of motor and motivational function, and it has been suggested that adenosine A 2A antagonists could be useful for the treatment of parkinsonism and depression. The present experiments were performed to characterize the effects of Lu AA47070, which is a phosphonooxymethylene prodrug of a potent and selective adenosine A 2A receptor antagonist, for its ability to reverse the motor and motivational effects of D2 antagonism. In the first group of studies, Lu AA47070 (3.75-30 mg/kg IP) was assessed for its ability to reverse the effects of the D2 receptor antagonist pimozide (1.0 mg/kg IP) using several measures of motor impairment, including catalepsy, locomotion, and tremulous jaw movements, which is a rodent model of parkinsonian tremor. Lu AA47070 produced a significant reversal of the effects of pimozide on all three measures of parkinsonian motor impairment. In addition, Lu AA47070 was able to reverse the effects of a low dose of the D2 antagonist haloperidol on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. The ability of Lu AA47070 to reverse the effects of D2 receptor blockade suggests that this compound could have potential utility as a treatment for parkinsonism, and for some of the motivational symptoms of depression.
机译:多巴胺D2和腺苷的2A受体相互作用以调节电动机和诱导功能的方面,并且已经提出了腺苷A 2A拮抗剂可用于治疗帕金森和抑郁症。进行本实验以表征Lu Aa47070的作用,即磷酸亚甲基前药,其效力和选择性腺苷的磷酸二甲基前药,其能够逆转D2拮抗作用的能力和促进效应。在第一组研究中,评估Lu Aa47070(3.75-30 mg / kg IP),以使用多种电机损伤措施逆转D2受体拮抗剂Pimozide(1.0mg / kg IP)的效果,包括透明症,运动和颤抖的下颚运动,这是帕金森震颤的啮齿动物模型。 Lu AA47070在Pimozide对Parkinsonian Motor损伤的所有三种措施产生了重大逆转。此外,Lu Aa47070能够逆转低剂量的D2拮抗剂氟哌啶醇在用作努力相关选择行为的衡量标准的同时压制/味道饲料任务上的影响。 Lu Aa47070逆转D2受体阻滞的效果的能力表明,这种化合物可以具有潜在的效用作为帕金森主义的治疗,以及一些抑郁症的诱导症状。

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