Cincinnati Veterans Affairs Medical Center, Psychiatry Service (V116A), 3200 Vine Street, Cincinnati, Ohio 45220, United States.
Physiol Behav. 2012 May 15;106(2):171-7. doi: 10.1016/j.physbeh.2012.02.004. Epub 2012 Feb 9.
Studies characterizing treatment interventions in a naturalistic setting suggest that antidepressant and antipsychotic medications may be equally effective in improving clinical outcome in individuals at high risk for first-episode psychosis. Of interest, both beneficial as well as potentially adverse effects have been observed following fluoxetine treatment in a mouse prenatal immune activation model of relevance to psychosis prevention. We sought to extend those findings by examining the effects of fluoxetine, as well as the antipsychotic medication aripiprazole, in a rat prenatal immune activation model.
Pregnant Sprague-Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline-treated dams received fluoxetine (10.0 mg/kg/d), aripiprazole (0.66 mg/kg/d), or vehicle from postnatal days 35 to 70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following drug discontinuation.
Both fluoxetine and aripiprazole had beneficial effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Significantly, both drugs also exerted effects in offspring of control (saline-treated) dams on locomotor response to injection.
Fluoxetine and aripiprazole pretreatment of poly I:C offspring from postnatal days 35 to 70 stabilized response to amphetamine exposure persisting through 3 months of age, similar to earlier findings in mice that fluoxetine treatment following prenatal immune activation prevented altered locomotor response to amphetamine. The current data also confirm earlier findings of potential adverse behavioral effects in offspring of control dams following treatment with fluoxetine and antipsychotic medications, highlighting the potential for both therapeutic as well as safety concerns with exposure to preventive pharmacological treatments over the course of adolescent development. Further study is needed to determine clinical and epidemiological consequences of these pre-clinical findings.
描述自然环境下治疗干预的研究表明，抗抑郁药和抗精神病药在改善首发精神病高危个体的临床结局方面可能同样有效。有趣的是，在与预防精神病相关的小鼠产前免疫激活模型中，氟西汀治疗后既观察到了有益作用，也观察到了潜在的不良反应。我们试图通过在大鼠产前免疫激活模型中检查氟西汀以及抗精神病药阿立哌唑的作用来扩展这些发现。
在妊娠第 14 天，给怀孕的 Sprague-Dawley 大鼠注射聚肌胞或生理盐水。聚肌胞和生理盐水处理的母鼠的后代从出生后第 35 天至第 70 天接受氟西汀（10.0mg/kg/d）、阿立哌唑（0.66mg/kg/d）或载体。在停药后 21 天，即三个月时，测定对新奇、生理盐水注射和安非他命（1 和 5mg/kg）的运动反应。
氟西汀和阿立哌唑均对三个月时安非他命（1mg/kg）的行为反应有有益作用，改善了产前免疫激活对聚肌胞处理的母鼠后代的影响。值得注意的是，两种药物在对照组（生理盐水处理）母鼠的后代中也对注射的运动反应产生了影响。
从出生后第 35 天至第 70 天，氟西汀和阿立哌唑预处理聚肌胞后代，稳定了对安非他命暴露的反应，持续到 3 个月大，类似于早期在产前免疫激活后氟西汀治疗预防安非他命运动反应改变的小鼠研究结果。当前的数据还证实了早期发现的氟西汀和抗精神病药物治疗对对照组母鼠后代潜在的不良行为影响，突出了在青少年发育过程中接触预防性药物治疗的潜在治疗和安全性问题。需要进一步研究以确定这些临床前发现的临床和流行病学后果。
