Preclinical Research, Targacept, Inc., Winston-Salem, NC 27101-4165, USA.
Med Hypotheses. 2012 May;78(5):594-600. doi: 10.1016/j.mehy.2012.01.035. Epub 2012 Feb 13.
The long prevailing hypothesis of schizophrenia pathogenesis implicates dopaminergic systems in the mesolimbic pathways as responsible for the positive symptoms of schizophrenia (hallucinations and delusions) and those in the mesocortical pathway as contributing to the negative symptoms (e.g., social disconnection, flattened affect and anhedonia). Several challenges to the dopamine hypothesis and the proposal of an alternative hypothesis implicating glutamate have provided additional support for the development of non-dopaminergic drugs for the management of schizophrenia symptomatology. Furthermore, preclinical and clinical evidence of alpha7 neuronal nicotinic acetylcholine receptor-mediated benefits in the triad of positive symptoms, negative symptoms and cognitive dysfunction in schizophrenia, as well as the genetic linkage of this receptor to the disease, have added another level of complexity. Thus schizophrenia is increasingly believed to involve multi-neurotransmitter deficits, all of which may contribute to altered dopaminergic tone in the mesolimbic, mesocortical and other areas of the brain. In this paper we provide a model that reconciles the dopamine, glutamate and alpha7 cholinergic etiopathogenesis and is consistent with the clinical benefit derived from therapies targeted to these individual pathways.
精神分裂症发病机制的长期流行假说表明，中脑边缘多巴胺能系统负责精神分裂症的阳性症状（幻觉和妄想），中脑皮质多巴胺能系统则导致阴性症状（如社交脱节、情感平淡和快感缺失）。多巴胺假说面临的一些挑战，以及涉及谷氨酸的替代假说的提出，为开发非多巴胺能药物治疗精神分裂症症状提供了更多支持。此外，精神分裂症阳性症状、阴性症状和认知功能障碍三联征中α7 神经元烟碱型乙酰胆碱受体介导的益处的临床前和临床证据，以及该受体与疾病的遗传联系，增加了另一个层面的复杂性。因此，精神分裂症越来越被认为涉及多种神经递质缺陷，所有这些都可能导致中脑边缘、中脑皮质和大脑其他区域多巴胺能张力的改变。在本文中，我们提出了一个模型，该模型调和了多巴胺、谷氨酸和α7 胆碱能的发病机制，与针对这些特定途径的治疗方法所带来的临床益处一致。
