Fischer S J, Arguello A A, Charlton J J, Fuller D C, Zachariou V, Eisch A J
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
Neuroscience. 2008 Feb 19;151(4):1217-24. doi: 10.1016/j.neuroscience.2007.11.035. Epub 2007 Dec 3.
Chronic morphine, administered via s.c. pellet, decreases the number of proliferating cells in the dentate gyrus subgranular zone (SGZ) in both rats and mice. This robust morphine-induced decrease could be used to better understand mechanisms regulating adult hippocampal neurogenesis, as well as to explore the relationship between neurogenesis and drug dependence, withdrawal, and relapse behaviors. Such research would benefit enormously from identifying a route of morphine administration that produces addiction-relevant blood levels of morphine, results in a high degree of dependence, translates to both rat and mouse, and is free of the behavioral confounds of s.c. pellets. Therefore, we examined a classic chronic morphine pellet paradigm (two s.c. pellets over 5 days) versus three chronic morphine injection paradigms (escalating dose i.p. injections over 2, 5, or 10 days) for their effect in adult male C57BL/6J mice. We assessed blood morphine levels, SGZ proliferation, and drug dependence as assessed by tolerance to locomotion sensitization and naloxone-precipitated withdrawal. The pellet paradigm produced high and relatively stable blood levels of morphine, a high degree of dependence, and a significant decrease in SGZ proliferation. In contrast, the three injection paradigms produced transient spikes in morphine blood levels, significantly less dependence than the pellet paradigm, and no significant decrease in SGZ proliferation. These data show that regulation of mouse SGZ proliferation requires high and relatively stable blood levels of morphine, and provide critical knowledge for the design of future studies to probe the relationship between addiction and neurogenesis.
通过皮下植入药丸给予慢性吗啡，会减少大鼠和小鼠齿状回颗粒下区（SGZ）中增殖细胞的数量。这种由吗啡引起的显著减少可用于更好地理解调节成体海马神经发生的机制，以及探索神经发生与药物依赖、戒断和复发行为之间的关系。通过确定一种能产生与成瘾相关的吗啡血药浓度、导致高度依赖性、适用于大鼠和小鼠且没有皮下植入药丸行为干扰的吗啡给药途径，此类研究将受益匪浅。因此，我们研究了经典的慢性吗啡药丸范式（5天内植入两颗皮下药丸）与三种慢性吗啡注射范式（分别在2天、5天或10天内腹腔注射递增剂量的吗啡）对成年雄性C57BL/6J小鼠的影响。我们评估了血中吗啡水平、SGZ增殖以及通过对运动敏化的耐受性和纳洛酮诱发的戒断反应评估的药物依赖性。药丸范式产生了高且相对稳定的吗啡血药浓度、高度依赖性以及SGZ增殖的显著减少。相比之下，三种注射范式导致吗啡血药水平出现短暂峰值，依赖性明显低于药丸范式，且SGZ增殖没有显著减少。这些数据表明，调节小鼠SGZ增殖需要高且相对稳定的吗啡血药浓度，并为未来探究成瘾与神经发生之间关系的研究设计提供了关键知识。
