Antipsychotic drugs require a treatment regimen of several weeks before clinical efficacy is achieved in patient populations. While the biochemical mechanisms underlying the delayed temporal profile remain unclear, molecular adaptations in specific neuroanatomical loci are likely involved. Haloperidol-induced changes in gene expression in various brain regions have been observed; however, alterations in distinct neuronal populations have remained elusive. The present study examined changes in gene expression profiles of ventral tegmental area (VTA) and substantia nigra (SN) tyrosine hydroxylase immunopositive neurons following 1, 10 or 21 days of haloperidol administration (0.5 mg/kg/day). Macroarrays were used to study the expression of receptors, signaling proteins, transcription factors and pre- and post-synaptic proteins. Data were analyzed using conventional statistical procedures as well as self-organizing maps (SOM) to elucidate conserved patterns of expression changes. Results show statistically significant haloperidol-induced and time-dependent alterations in 17 genes in the VTA and 25 genes in the SN, including glutamate and GABA receptor subunits, signaling proteins and transcription factors. SOMs revealed distinct patterns of gene expression changes in response to haloperidol. Understanding how gene expression is altered over a clinically relevant time course of haloperidol administration may provide insight into the development of antipsychotic efficacy as well as the underlying pathology of schizophrenia.
展开▼
机译：抗精神病药需要数周的治疗方案，才能在患者人群中达到临床疗效。虽然目前尚不清楚延迟的时间概况背后的生化机制，但可能涉及特定神经解剖学位点的分子适应。有人观察到氟哌啶醇可引起大脑各个区域基因表达的改变。然而，不同神经元群体的改变仍然难以捉摸。本研究研究了氟哌啶醇给药1、10或21天（0.5 mg / kg /天）后腹侧被盖区（VTA）和黑质（SN）酪氨酸羟化酶免疫阳性神经元基因表达谱的变化。宏阵列用于研究受体，信号蛋白，转录因子以及突触前和突触后蛋白的表达。使用常规统计程序以及自组织图（SOM）分析数据，以阐明表达变化的保守模式。结果显示，氟哌啶醇诱导的VTA中的17个基因和SN中的25个基因具有统计学意义的时变变化，包括谷氨酸和GABA受体亚基，信号蛋白和转录因子。 SOMs揭示了对氟哌啶醇响应的基因表达变化的不同模式。了解氟哌啶醇在临床相关时间段内基因表达的变化是如何为抗精神病药功效的发展以及精神分裂症的潜在病理学提供洞察力的。
展开▼
