Aranda Gissel P, Hinojos Samantha J, Sabandal Paul R, Evans Peter D, Han Kyung-An
Neuromodulation Disorders Cluster at Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El PasoEl Paso, TX, United States.
The Inositide Laboratory, The Babraham InstituteCambridge, United Kingdom.
Front Syst Neurosci. 2017 Aug 2;11:56. doi: 10.3389/fnsys.2017.00056. eCollection 2017.
Male flies under the influence of ethanol display disinhibited courtship, which is augmented with repeated ethanol exposures. We have previously shown that dopamine is important for this type of ethanol-induced behavioral sensitization but the underlying mechanism is unknown. Here we report that DopEcR, an insect G-protein coupled receptor that binds to dopamine and steroid hormone ecdysone, is a major receptor mediating courtship sensitization. Upon daily ethanol administration, and mutant males defective in D1 (dDA1/DopR1) and D5 (DAMB/DopR2) dopamine receptors, respectively, showed normal courtship sensitization; however, the DopEcR-deficient males exhibited greatly diminished sensitization. mutant males nevertheless developed normal tolerance to the sedative effect of ethanol, indicating a selective function of DopEcR in chronic ethanol-associated behavioral plasticity. DopEcR plays a physiological role in behavioral sensitization since courtship sensitization in males was reinstated when DopEcR expression was induced during adulthood but not during development. When examined for the DopEcR's functional site, the mutant's sensitization phenotype was fully rescued by restored DopEcR expression in the mushroom body (MB) αβ and γ neurons. Consistently, we observed DopEcR immunoreactivity in the MB calyx and lobes in the wild-type brain, which was barely detectable in the brain. Behavioral sensitization to the locomotor-stimulant effect has been serving as a model for ethanol abuse and addiction. This is the first report elucidating the mechanism underlying behavioral sensitization to another stimulant effect of ethanol.
受乙醇影响的雄性果蝇表现出不受抑制的求偶行为，且随着乙醇暴露次数的增加而增强。我们之前已经表明多巴胺对于这种类型的乙醇诱导的行为敏化很重要，但潜在机制尚不清楚。在此我们报告，DopEcR，一种与多巴胺和类固醇激素蜕皮激素结合的昆虫G蛋白偶联受体，是介导求偶敏化的主要受体。每天给予乙醇后，分别在D1（dDA1/DopR1）和D5（DAMB/DopR2）多巴胺受体有缺陷的突变雄性果蝇表现出正常的求偶敏化；然而，DopEcR缺陷的果蝇雄性表现出极大减弱的敏化。不过，突变雄性果蝇对乙醇的镇静作用仍产生了正常的耐受性，这表明DopEcR在慢性乙醇相关行为可塑性中具有选择性功能。DopEcR在行为敏化中发挥生理作用，因为当在成年期而非发育期间诱导DopEcR表达时，果蝇雄性的求偶敏化得以恢复。当检查DopEcR的功能位点时，通过在蘑菇体（MB）αβ和γ神经元中恢复DopEcR表达，突变体的敏化表型得到了完全挽救。一致地，我们在野生型果蝇大脑的MB花萼和叶中观察到DopEcR免疫反应性，而在果蝇大脑中几乎检测不到。对运动刺激作用的行为敏化一直被用作乙醇滥用和成瘾的模型。这是第一份阐明对乙醇另一种刺激作用的行为敏化潜在机制的报告。
