Osuna-Luque Jaime, Rodríguez-Ramos Ángel, Gámez-Del-Estal María Del Mar, Ruiz-Rubio Manuel
Department of Genetics, University of Córdoba, Córdoba, Spain.
Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain.
J Exp Neurosci. 2018 Sep 18;12:1179069518798628. doi: 10.1177/1179069518798628. eCollection 2018.
The neurotransmitters dopamine and serotonin participate in specific behavioral neuromuscular mechanisms in the nematode . Dopamine is involved in the gentle touch response and serotonin in the pharyngeal pumping rate. In its genome, the worm presents genes encoding dopamine and serotonin receptors orthologous to those of human genes. Risperidone and aripiprazole are a class of drugs known as atypical antipsychotics commonly used to treat schizophrenia, bipolar disorder, and irritability associated with autism. Risperidone is an antagonist of the dopamine D2 and serotonin 5-HT2A receptors. Aripiprazole functions as a partial agonist of the dopamine D2 receptor and as a partial agonist and antagonist of 5-HT1A and 5-HT2A serotonin receptors, respectively. Our results show that risperidone and aripiprazole alter the touch response and pharyngeal pumping in wild-type worm animals. Furthermore, in the presence of the drugs, both behaviors change to varying degrees in dopamine (, and ), serotonin (), and tyramine () receptor-deficient mutants. This variation in response reveals specific targets for these antipsychotics in the nematode. Interestingly, their effect on behavior persisted to some extent in successive generations, indicating that they might induce epigenetic changes throughout development. Sodium butyrate, a histone deacetylase inhibitor, eliminated the consecutive generation effect of both drugs. In addition, these transgenerational effects were also abolished after the dauer stage. These observations suggest that risperidone and aripiprazole, in addition to interacting with specific receptors impairing the function of the nervous system of the nematode, may lead to the deposition of long-lasting epigenetic marks.
神经递质多巴胺和血清素参与线虫特定的行为神经肌肉机制。多巴胺参与轻触反应，血清素则与咽部泵血速率有关。线虫的基因组中存在编码与人类基因直系同源的多巴胺和血清素受体的基因。利培酮和阿立哌唑是一类被称为非典型抗精神病药物，常用于治疗精神分裂症、双相情感障碍以及与自闭症相关的易怒症状。利培酮是多巴胺D2和血清素5-HT2A受体的拮抗剂。阿立哌唑分别作为多巴胺D2受体的部分激动剂以及血清素5-HT1A和5-HT2A受体的部分激动剂和拮抗剂发挥作用。我们的研究结果表明，利培酮和阿立哌唑会改变野生型线虫动物的触觉反应和咽部泵血。此外，在药物存在的情况下，多巴胺（ 、 和 ）、血清素（ ）和酪胺（ ）受体缺陷型突变体的这两种行为均会发生不同程度的变化。这种反应差异揭示了这些抗精神病药物在线虫中的特定作用靶点。有趣的是，它们对行为的影响在连续几代中都在一定程度上持续存在，这表明它们可能在整个发育过程中诱导表观遗传变化。组蛋白脱乙酰酶抑制剂丁酸钠消除了这两种药物的连续代效应。此外，在滞育期后，这些跨代效应也被消除。这些观察结果表明，利培酮和阿立哌唑除了与特定受体相互作用损害线虫神经系统功能外，可能还会导致持久表观遗传标记的沉积。
