Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Department of Neuroscience, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy.
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):184-97. doi: 10.1016/j.pnpbp.2010.10.025. Epub 2010 Nov 3.
The detection of changes in postsynaptic gene expression after the administration of mood stabilizers, alone or in combination with antipsychotics, and antidepressants in animal models of drug treatment, may represent a valuable strategy to explore the molecular targets of the mainstay treatments for bipolar disorder. In this study we investigated, in both acute and chronic paradigms, the expression of specific postsynaptic density genes (Homer1a, Homer1b/c, and PSD95) and genes putatively implicated in mood stabilizers mechanism of action (GSK3b, ERK) after administration of first (haloperidol) or second generation antipsychotics (quetiapine 30 mg/kg), alone or in combination with valproate. Moreover, we compared the effects of an antidepressant agent widely used in bipolar depression (citalopram) with a low dose of quetiapine (15 mg/kg), which has been demonstrated to display antidepressant action in bipolar depression. In striatal regions, Homer1a expression was strongly induced by haloperidol compared to all the other treatments. Haloperidol plus valproate also markedly induced Homer1a, but to a significant lesser extent than haloperidol alone. Also in the chronic paradigm haloperidol, but not haloperidol plus valproate, induced Homer1a expression in all the subregions of the caudate-putamen and in the nucleus accumbens core. The high dose of quetiapine significantly induced Homer1a in anterior cingulated, premotor and motor subregions of the cortex, and the extent of induction was significantly higher as compared to the lower dose. Oppositely, Homer1a expression was decreased in the cortex by citalopram acute administration. ERK gene was upregulated in cortex and striatum by the acute treatment with valproate and with the combination of haloperidol or quetiapine plus valproate, whereas no significant differences were noticed in GSK3b expression among treatments. PSD95 showed a significant upregulation by acute citalopram and by haloperidol plus valproate in both cortical and subcortical regions. Haloperidol and quetiapine 30 mg/kg, oppositely, significantly reduced the expression of the gene in the cortex. In conclusion, these results suggest that the combined treatment with a typical or an atypical antipsychotic plus valproate may induce differential modulation of postsynaptic genes expression when compared to the effects of these drugs individually administered.
在药物治疗的动物模型中，检测心境稳定剂、抗精神病药和抗抑郁药单独或联合应用后突触后基因表达的变化，可能代表了探索双相情感障碍主要治疗方法的分子靶点的一种有价值的策略。在这项研究中，我们在急性和慢性模型中研究了特定的突触后密度基因（ Homer1a、Homer1b/c 和 PSD95）和可能与心境稳定剂作用机制相关的基因（GSK3b、ERK）的表达，这些基因在单独或联合使用第一代（氟哌啶醇）或第二代抗精神病药（喹硫平 30mg/kg），单独或联合使用丙戊酸钠后。此外，我们比较了一种广泛用于双相抑郁的抗抑郁药（西酞普兰）和一种低剂量喹硫平（15mg/kg）的作用，后者已被证明在双相抑郁中有抗抑郁作用。在纹状体区域，与其他所有治疗相比，氟哌啶醇强烈诱导 Homer1a 的表达。氟哌啶醇加丙戊酸钠也显著诱导 Homer1a，但程度明显低于氟哌啶醇单独使用。在慢性模型中，氟哌啶醇，但不是氟哌啶醇加丙戊酸钠，诱导了尾状核和伏隔核核心的所有亚区 Homer1a 的表达。高剂量喹硫平显著诱导了前扣带皮层、前运动皮层和运动皮层的 Homer1a 表达，诱导程度明显高于低剂量。相反，西酞普兰急性给药会导致皮层 Homer1a 的表达减少。ERK 基因在皮层和纹状体中被丙戊酸钠的急性处理和氟哌啶醇或喹硫平加丙戊酸钠的联合处理上调，而 GSK3b 的表达在处理之间没有显著差异。PSD95 在皮质和皮质下区域中，由急性西酞普兰和氟哌啶醇加丙戊酸钠处理显著上调。相反，氟哌啶醇和喹硫平 30mg/kg 显著降低了皮质中的基因表达。总之，这些结果表明，与这些药物单独给药相比，联合使用典型或非典型抗精神病药加丙戊酸钠可能会导致突触后基因表达的差异调节。
