Mehler-Wex C, Riederer P, Gerlach M
Department of Child and Adolescent Psychiatry and Psychotherapy, Julius-Maximilians-University, Wuerzburg, Germany.
Neurotox Res. 2006 Dec;10(3-4):167-79. doi: 10.1007/BF03033354.
The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.
基底神经节构成一个前脑系统，该系统收集来自大部分新皮层的信号，对这些皮层输入信号进行相互之间以及相对于来自边缘系统输入信号的重新分配，然后将这种重新分配并整合后的信号输入集中到额叶和脑干的特定区域，这些区域参与运动规划和运动记忆的各个方面。与基底神经节功能障碍相关的运动障碍包括一系列异常情况，从一端的运动减少性障碍（帕金森病，PD，是最著名的例子）到另一端的运动增多性障碍（以亨廷顿舞蹈病和偏身投掷症为例）。除了运动障碍外，包括精神分裂症样状态和注意力缺陷多动障碍（ADHD）在内的主要精神障碍也与基底神经节及其相关核团的异常有关。在本文中，我们讨论了最近的证据，表明多巴胺诱导的基底神经节神经回路失衡可能是帕金森病、精神分裂症和注意力缺陷多动障碍重要的病理生理组成部分。根据我们的模型，如在帕金森病中那样，多巴胺能黑质 -纹状体输入的缺失减少了通过直接系统的正反馈，并增加了通过间接系统的负反馈。关键后果是基底神经节输出部位过度活跃，从而抑制丘脑 -皮层驱动。在精神分裂症中，严重的认知缺陷可能部分是抑制性多巴胺D(2)传递系统过度活跃的结果。通过这种去抑制作用，丘脑表现出过度活跃，过度刺激皮层，导致感知、注意力、刺激辨别、信息处理和情感调节功能障碍（引发幻觉和妄想）以及运动障碍。最近的研究强烈表明，多巴胺能系统的紊乱也参与了注意力缺陷多动障碍的病理生理过程。最有说服力的证据来自于多巴胺转运体（DAT）阻滞剂哌甲酯等精神兴奋剂在注意力缺陷多动障碍症状治疗中的疗效证明。基因研究表明注意力缺陷多动障碍与参与多巴胺能神经传递的基因之间存在关联（例如多巴胺受体基因DRD4和DRD5，以及DAT基因DAT1）。DAT基因敲除小鼠表现出运动活动增加的表型，而精神兴奋剂治疗可使其恢复正常。最后，影像学研究表明注意力缺陷多动障碍患者纹状体中DAT密度增加。目前尚不清楚哪个系统受到干扰，以及该系统是过度活跃还是活动不足。
