Laboratório de Genética Toxicológica, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, ULBRA, Bairro São José, Canoas, RS, Brazil.
Acta Pharmacol Sin. 2011 Oct;32(10):1225-32. doi: 10.1038/aps.2011.77. Epub 2011 Aug 15.
Aripiprazole is an antipsychotic agent to treat schizophrenia, which acts through dopamine D(2) partial agonism, serotonin 5-HT(1A) partial agonism and 5-HT(2A) antagonism. This study was designed to evaluate the neurobehavioral effects and genotoxic/mutagenic activities of the agent, as well as its effects on lipoperoxidation.
Open field and inhibitory avoidance tasks were used. Thirty min before performing the behavioral tasks, adult male CF-1 mice were administered aripiprazole (1, 3 or 10 mg/kg, ip) once for the acute treatment, or the same doses for 5 d for the subchronic treatment. Genotoxic effects were assessed using comet assay in the blood and brain tissues. Mutagenic effects were evaluated using bone marrow micronucleus test. Lipoperoxidation was assessed with thiobarbituric acid reactive substances (TBARS).
Acute and subchronic treatments significantly decreased the number of crossing and rearing in the open field task. Acute treatment significantly increased the step-down latency for both the short- and long-term memory in the inhibitory avoidance task. Subchronic treatments with aripiprazole (3 and 10 mg/kg) caused significant DNA strain-break damage in peripheral blood but not in the brain. Mutagenic effect was not detected in the acute and subchronic treatments. Nor TBARS levels in the liver were affected.
Aripiprazole improved memory, but could impair motor activities in mice. The drug increased DNA damage in blood, but did not show mutagenic effects, suggesting that it might affect long-term genomic stability.
阿立哌唑是一种用于治疗精神分裂症的抗精神病药物，其作用机制为多巴胺 D(2)部分激动、5-羟色胺 5-HT(1A)部分激动和 5-HT(2A)拮抗。本研究旨在评估该药物的神经行为效应、遗传毒性/致突变活性及其对脂质过氧化的影响。
采用旷场实验和抑制性回避实验。在进行行为任务前 30 min，成年雄性 CF-1 小鼠一次性给予阿立哌唑（1、3 或 10 mg/kg，ip）进行急性处理，或相同剂量连续 5 d 进行亚慢性处理。采用彗星实验检测血液和脑组织中的遗传毒性，采用骨髓微核实验检测致突变活性，采用硫代巴比妥酸反应物（TBARS）检测脂质过氧化。
急性和亚慢性处理均显著降低旷场实验中动物的穿越和站立次数。急性处理显著增加抑制性回避任务中短期和长期记忆的下跳潜伏期。阿立哌唑（3 和 10 mg/kg）亚慢性处理导致外周血中 DNA 链断裂损伤显著增加，但对大脑无影响。急性和亚慢性处理均未检测到致突变作用。肝脏中的 TBARS 水平也不受影响。
阿立哌唑改善了记忆，但可损害小鼠的运动活动。该药物增加了血液中的 DNA 损伤，但未显示致突变作用，提示其可能影响长期基因组稳定性。
