Conn P Jeffrey, Tamminga Carol, Schoepp Darryle D, Lindsley Craig
Vanderbilt University, Department of Pharmacology, Nashville, TN 37232, USA.
Mol Interv. 2008 Apr;8(2):99-107. doi: 10.1124/mi.8.2.7.
Schizophrenia is a disabling psychiatric disorder characterized by positive, negative, and cognitive symptoms. The first pharmacological treatments for schizophrenia were discovered by serendipitous, albeit carefully documented, clinical observations. The discovery of chlorpromazine and other dopamine D2 receptor antagonists as antipsychotic agents set the early course of drug discovery in the context of schizophrenia and other psychiatric disorders, and various monoamine receptors became the prime focus of neuropharmacological studies. Success in treating the positive symptoms nevertheless remained limited by the general lack of efficacy in addressing negative symptoms and cognitive impairment. In recent years, several new experimental approaches have emerged for the identification and treatment of different symptom clusters that do not rely on blockade of monoamine receptors. Muscarinic, nicotinic, and glutamatergic signaling mechanisms have become essential to neuropharmacological and behavioral models of discrete aspects of schizophrenia. And as a consequence of these insights, novel drug entities have become available to study and potentially treat the disabling cognitive and negative symptoms of psychiatric disease. Current attempts to target a new range of receptors entail unprecedented fine-tuning in the pharmacological manipulation of specific receptor subtypes.
精神分裂症是一种致残性精神障碍，其特征为阳性、阴性和认知症状。精神分裂症的首批药物治疗方法是通过偶然发现的，尽管有详细记录的临床观察发现的。氯丙嗪和其他多巴胺D2受体拮抗剂作为抗精神病药物的发现，为精神分裂症和其他精神障碍背景下的药物发现奠定了早期基础，各种单胺受体成为神经药理学研究的主要焦点。然而，在治疗阴性症状和认知障碍方面普遍缺乏疗效，这仍然限制了对阳性症状的治疗效果。近年来，出现了几种新的实验方法来识别和治疗不同的症状群，这些方法不依赖于单胺受体的阻断。毒蕈碱、烟碱和谷氨酸能信号传导机制已成为精神分裂症离散方面的神经药理学和行为模型的关键。由于这些见解，新型药物实体已可用于研究并有可能治疗精神疾病中致残性的认知和阴性症状。目前针对一系列新受体的尝试需要在特定受体亚型的药理操作方面进行前所未有的精细调整。
