Epigenetic modulation of antipsychotic-induced side effects in aged mice

在老年人群中使用精神药物总是具有挑战性，因为疗效降低和副作用加剧。因此，迫切需要寻找新的有效方法来提高抗精神病药物的疗效并减少对老年人的副作用。年龄相关的变化表观遗传调节可能有助于抗精神病药物诱导的适当基因表达的恶化。先前的研究表明，抗精神病药物的主要靶点--多巴胺的受体功能在衰老过程中的中断可能是由于基因表达的变化。与年龄相关的多巴胺能系统内稳态张力的变化可能是由表观遗传机制介导的，从而揭示了通过药物治疗干预这些影响的潜在可逆性。在本研究中，我们将探讨(1)是否由于组蛋白低乙酰化和高甲基化而导致纹状体和皮质多巴胺2(D2)受体(mRNA和蛋白水平)的增龄相关降低；(2)是否由于抗精神病药物在老龄小鼠中的生理和行为敏感性降低，D2基因和蛋白表达降低，D2受体占有率降低；(3)HDAC抑制剂(丙戊酸(VPA)和伏立诺(SAHA))联合治疗是否会通过逆转衰老相关的表观遗传效应来减少氟哌啶醇(HAL)诱导的锥体外系副作用(EPS)。我们的初步发现显示，HAL与VPA联合治疗可逆转纹状体DRD2启动子区域与年龄相关的低乙酰化，该区域与D2受体蛋白表达降低相关。这些变化与HAL诱导的EPS行为减少有关。这些发现与论文建议一起，将表明衰老是否减少了纹状体和前额叶皮质中的组蛋白乙酰化并增加了组蛋白三甲基化水平，从而干扰了与EPS减少相关的D2受体的调节。我们的研究将提供分子、细胞、药理学和行为学证据，表明与年龄相关的组蛋白修饰影响抗精神病药物的特性，揭示衰老、表观遗传调节和抗精神病药物作用之间的联系。这项建议将有助于为老年人，特别是那些患有精神障碍的人开发新的治疗策略。

The use of psychotropic medications in the elderly population is always challenging due to decreased efficacy and an exacerbated side effects. Thus, there is an urgent need to find new and efficient ways to increase efficacy and to decrease side effects of antipsychotics for aged individuals. Age-related changes epigenetic modulation may contribute to the deterioration of appropriate gene expression induced by antipsychotics. Previous studies have suggested that disruption in receptor functions of dopamine during aging, the primary target of antipsychotic drugs, may be due to changes in gene expression. Age-related changes in the homeostatic tone of the dopaminergic system may be mediated by epigenetic mechanisms, thus revealing a potential reversibility of these effects by pharmacological therapeutic intervention. For this study, we will investigate (1) if age-related decrease of striatal and cortical dopamine 2 (D2) receptor (mRNA and protein levels) are due to histone hypoacetylation and hypermethylation; (2) if increased physiological and behavioral sensitivity to antipsychotic drugs in aged mice is due to decreased D2 gene and protein expression and decreased D2 receptor occupancy and (3) if co-treatment of HDAC inhibitors (valproic acid (VPA) and vorinostat (SAHA)) will decrease haloperidol (HAL)-induced extrapyramidal side effects (EPS) in aged mice by reversing age-related epigenetic effects. Our preliminary findings revealed that co-treatment of HAL with VPA reverses age-related hypoacetylation at the striatal Drd2 promoter region that correlates with decreased D2 receptor protein expression. These changes are associated with decreased HAL-induced EPS behavior. These findings, together with the dissertation proposal, will indicate whether aging reduces histone acetylation and increases histone tri-methylation levels in the striatum and prefrontal cortex that subsequently interfere with the regulation of D2 receptor which is relevant for reduction of EPS. Our study will provide molecular, cellular, pharmacological and behavioral evidence showing that age-related histone modifications affect antipsychotic properties, uncovering the links between aging, epigenetic modulation and antipsychotic drug action. This proposal will help to develop novel therapeutic strategy for aged people, particularly those that suffer from psychiatric disorders.