van der Marel K, Bouet V, Meerhoff G F, Freret T, Boulouard M, Dauphin F, Klomp A, Lucassen P J, Homberg J R, Dijkhuizen R M, Reneman L
Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
Normandie Univ, UCBN, Groupe Mémoire et Plasticité comportementale (GMPc) EA 4259, UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, France.
Neuroscience. 2015 Nov 19;309:243-58. doi: 10.1016/j.neuroscience.2015.04.044. Epub 2015 Apr 28.
Methylphenidate (MPH) is a widely prescribed stimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Its use in this age group raises concerns regarding the potential interference with ongoing neurodevelopmental processes. Particularly the hippocampus is a highly plastic brain region that continues to develop postnatally and is involved in cognition and emotional behavior, functions known to be affected by MPH. In this study, we assessed whether hippocampal structure and function were affected by chronic oral MPH treatment and whether its effects were different in adolescent or adult rats. Using behavioral testing, resting-state functional MRI, post-mortem structural magnetic resonance imaging (MRI), and immunohistochemistry, we assessed MPH's effects on recognition memory, depressive-like behavior, topological features of functional connectivity networks, hippocampal shape and markers for hippocampal neurogenesis and proliferation. Object recognition memory was transiently impaired in adolescent treated rats, while in animals treated during adulthood, increased depressive-like behavior was observed. Neurogenesis was increased in adolescent treated rats, whereas cell proliferation was decreased following adult treatment. Adolescent treated rats showed inward shape deformations adjacent to ventral parahippocampal regions known to be involved in recognition memory, whereas such deformations were not observed in adult treated animals. Irrespective of the age of treatment, MPH affected topological features of ventral hippocampal functional networks. Thus, chronic oral treatment with a therapeutically relevant dose of MPH preferentially affected the ventral part of the hippocampus and induced contrasting effects in adolescent and adult rats. The differences in behavior were paralleled by opposite effects on adult neurogenesis and granule cell proliferation.
哌甲酯（MPH）是一种广泛用于治疗儿童和青少年注意力缺陷多动障碍（ADHD）的兴奋性药物。在这个年龄组中使用该药物引发了人们对其可能干扰正在进行的神经发育过程的担忧。特别是海马体是一个高度可塑性的脑区，在出生后仍持续发育，并参与认知和情绪行为，而这些功能已知会受到MPH的影响。在本研究中，我们评估了慢性口服MPH治疗是否会影响海马体的结构和功能，以及其在青春期或成年大鼠中的作用是否不同。通过行为测试、静息态功能磁共振成像（MRI）、死后结构磁共振成像（MRI）和免疫组织化学，我们评估了MPH对识别记忆、抑郁样行为、功能连接网络的拓扑特征、海马体形状以及海马体神经发生和增殖标志物的影响。在青春期接受治疗的大鼠中，物体识别记忆暂时受损，而在成年期接受治疗的动物中，观察到抑郁样行为增加。青春期接受治疗的大鼠神经发生增加，而成年期治疗后细胞增殖减少。青春期接受治疗的大鼠在已知参与识别记忆的腹侧海马旁区域附近出现向内的形状变形，而在成年期接受治疗的动物中未观察到这种变形。无论治疗年龄如何，MPH都会影响腹侧海马体功能网络的拓扑特征。因此，以治疗相关剂量进行慢性口服MPH治疗优先影响海马体的腹侧部分，并在青春期和成年大鼠中产生相反的效果。行为上的差异与对成年神经发生和颗粒细胞增殖的相反影响平行。
