Terry A V, Gearhart D A, Warner S E, Zhang G, Bartlett M G, Middlemore M-L, Beck W D, Mahadik S P, Waller J L
Department of Pharmacology and Toxicology, CB-3618, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA 30912-2300, USA.
Neuroscience. 2007 May 25;146(3):1316-32. doi: 10.1016/j.neuroscience.2007.03.003. Epub 2007 Apr 16.
First and second generation antipsychotics (FGAs and SGAs) ameliorate psychotic symptoms of schizophrenia, however, their chronic effects on information processing and memory function (i.e. key determinants of long term functional outcome) are largely unknown. In this rodent study the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the FGA, haloperidol (2.0 mg/kg/day), or the SGA, risperidone (2.5 mg/kg/day) on a water maze repeated acquisition procedure, the levels of nerve growth factor receptors, and two important cholinergic proteins, the vesicular acetylcholine transporter and the high affinity choline transporter were evaluated. The effects of the antipsychotics on a spontaneous novel object recognition procedure were also assessed during days 8-14 and 31-38 of treatment. Haloperidol (but not risperidone) was associated with impairments in water maze hidden platform trial performance at each of the time periods evaluated up to 45 days, but not when tested during days 83-90. In contrast, risperidone did not impair water maze task performance at the early time periods and it was actually associated with improved performance during the 83-90 day period. Both antipsychotics, however, were associated with significant water maze impairments during the 174-180 day period. Further, haloperidol was associated with decrements in short delay performance in the spontaneous novel object recognition task during both the 8-14 and 31-38 day periods of treatment, while risperidone was associated with short delay impairment during the 31-38 day time period. Both antipsychotics were also associated with time dependent alterations in the vesicular acetylcholine transporter, the high affinity choline transporter, as well as tyrosine kinase A, and p75 neurotrophin receptors in specific brain regions. These data from rats support the notion that while risperidone may hold some advantages over haloperidol, both antipsychotics can produce time-dependent alterations in neurotrophin receptors and cholinergic proteins as well as impairments in the performance of tasks designed to assess spatial learning and episodic memory.
第一代和第二代抗精神病药物（FGA和SGA）可改善精神分裂症的精神病症状，然而，它们对信息处理和记忆功能（即长期功能预后的关键决定因素）的长期影响在很大程度上尚不清楚。在这项啮齿动物研究中，评估了用FGA氟哌啶醇（2.0毫克/千克/天）或SGA利培酮（2.5毫克/千克/天）进行不同时间段（从2周至6个月）口服治疗对水迷宫重复获取程序、神经生长因子受体水平以及两种重要的胆碱能蛋白（囊泡乙酰胆碱转运体和高亲和力胆碱转运体）的影响。在治疗的第8 - 14天和第31 - 38天期间，还评估了抗精神病药物对自发新颖物体识别程序的影响。在长达45天的每个评估时间段内，氟哌啶醇（而非利培酮）与水迷宫隐藏平台试验表现受损有关，但在第83 - 90天进行测试时则不然。相比之下，利培酮在早期时间段并未损害水迷宫任务表现，实际上在第83 - 90天期间其与表现改善有关。然而，在第174 - 180天期间，两种抗精神病药物均与明显的水迷宫损害有关。此外，在治疗的第8 - 14天和第31 - 38天期间，氟哌啶醇与自发新颖物体识别任务中的短延迟表现下降有关，而利培酮在第31 - 38天时间段与短延迟损害有关。两种抗精神病药物还与特定脑区中囊泡乙酰胆碱转运体、高亲和力胆碱转运体以及酪氨酸激酶A和p75神经营养因子受体的时间依赖性改变有关。来自大鼠的这些数据支持这样一种观点，即虽然利培酮可能比利培酮具有一些优势，但两种抗精神病药物均可在神经营养因子受体和胆碱能蛋白中产生时间依赖性改变，以及在旨在评估空间学习和情景记忆的任务表现中造成损害。
