Parikh Vinay, Khan Mohammad M, Terry Alvin, Mahadik Sahebarao P
Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia, USA.
J Psychiatr Res. 2004 Sep-Oct;38(5):521-9. doi: 10.1016/j.jpsychires.2004.03.008.
Previously we reported that chronic exposure to haloperidol (HAL), but not the atypical antipsychotics risperidone (RISP) or clozapine (CLOZ), resulted in reductions in brain choline acetyltransferase (ChAT) immunoreactivity and impaired water maze task performance in rats. In the present study, we compared the effects of these antipsychotic drugs on the expression of nerve growth factor (NGF) as well ChAT the in the rat cortex and nucleus basalis of Meynert (NBM) in an effort to determine the underlying mechanism for the differential drug effects observed previously. We also evaluated the effects of these compounds in a crossover design to evaluate specific neurochemical consequences of switching between typical and atypical antipsychotics, a common practice observed in the clinical setting. Male Wistar rats (250-300 g) were exposed to HAL (2.0 mg/kg/day), RISP (2.5 mg/kg/day), or CLOZ (20 mg/kg/day) for 45 days or a pre-treatment regimen consisting of administering either RISP/HAL (i.e., RISP followed by HAL) or CLOZ/HAL, or a post-treatment regimen consisting of administering: HAL/RISP or HAL/CLOZ. The duration of each treatment in the crossover study was also 45 days. NGF and ChAT immunoreactivity were measured by quantitative immunohistochemistry in some sub-cerebral cortical regions and NBM after drug exposures. NGF protein was also measured by an enzyme-linked ImmunoSorbent assay (ELISA) in rat sensorimotor cortex. The results indicated that HAL (but not RISP or CLOZ) significantly reduced NGF levels in some sub-cortical regions and ChAT immunoreactivity in both cortex and NBM. However, pre-treatment with CLOZ prevented the HAL-associated decreases in NGF and ChAT, while post-treatment with either RISP or CLOZ (i.e., after the administration of HAL) appeared to restore NGF and ChAT to control levels. These data indicate that antipsychotic drugs exert dissimilar effects on the levels of NGF and ChAT in the brain, which may contribute to their differential effects on cognitive function. The crossover data further suggest that certain atypical antipsychotic drugs (e.g., clozapine) may have the potential to prevent or reverse the deleterious effects of HAL on important neurochemical substrates of cognitive function.
我们之前报道过，长期暴露于氟哌啶醇（HAL），而非非典型抗精神病药物利培酮（RISP）或氯氮平（CLOZ），会导致大鼠脑内胆碱乙酰转移酶（ChAT）免疫反应性降低，并损害其水迷宫任务表现。在本研究中，我们比较了这些抗精神病药物对大鼠皮质和Meynert基底核（NBM）中神经生长因子（NGF）以及ChAT表达的影响，以确定先前观察到的药物差异效应的潜在机制。我们还采用交叉设计评估了这些化合物的作用，以评估在典型和非典型抗精神病药物之间转换的特定神经化学后果，这在临床环境中是一种常见做法。雄性Wistar大鼠（250 - 300克）暴露于HAL（2.0毫克/千克/天）、RISP（2.5毫克/千克/天）或CLOZ（20毫克/千克/天）45天，或接受由RISP/HAL（即先给予RISP后给予HAL）或CLOZ/HAL组成的预处理方案，或接受由HAL/RISP或HAL/CLOZ组成的后处理方案。交叉研究中每种处理的持续时间也为45天。在药物暴露后，通过定量免疫组织化学法在一些大脑皮质下区域和NBM中测量NGF和ChAT免疫反应性。还通过酶联免疫吸附测定（ELISA）法在大鼠感觉运动皮质中测量NGF蛋白。结果表明，HAL（而非RISP或CLOZ）显著降低了一些皮质下区域的NGF水平以及皮质和NBM中的ChAT免疫反应性。然而，用CLOZ进行预处理可防止HAL引起的NGF和ChAT降低，而用RISP或CLOZ进行后处理（即在给予HAL之后）似乎可使NGF和ChAT恢复到对照水平。这些数据表明，抗精神病药物对脑内NGF和ChAT水平产生不同影响，这可能导致它们对认知功能产生差异效应。交叉研究数据进一步表明，某些非典型抗精神病药物（如氯氮平）可能有潜力预防或逆转HAL对认知功能重要神经化学底物的有害影响。
