Hensler Julie G, Artigas Francesc, Bortolozzi Analía, Daws Lynette C, De Deurwaerdère Philippe, Milan Léa, Navailles Sylvia, Koek Wouter
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Adv Pharmacol. 2013;68:167-97. doi: 10.1016/B978-0-12-411512-5.00009-9.
This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5-HT1A receptors. The hallmark of Parkinson's disease is the destruction of nigrostriatal dopaminergic neurons. l-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by l-DOPA and offer opportunities to improve l-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative.
本章汇集了几个顶尖实验室的研究成果，每个实验室都是针对中枢神经系统复杂疾病采用综合方法的杰出典范。与精神分裂症相关的认知功能障碍和阴性症状被认为是中脑皮质多巴胺能投射到前额叶皮质（PFC）功能减退所致。增强PFC中多巴胺能功能的去甲肾上腺素能靶点有望改善认知缺陷以及阴性症状。调节中脑皮质多巴胺能神经传递的5-羟色胺能靶点包括5-HT2A和5-HT1A受体。帕金森病的标志是黑质纹状体多巴胺能神经元的破坏。左旋多巴是多巴胺的代谢前体，是治疗的标准药物。然而，5-羟色胺神经元中多巴胺（DA）的异位释放以及富含去甲肾上腺素能终末区域中去甲肾上腺素转运体对细胞外DA的清除，导致了左旋多巴产生的细胞外DA，并为改善左旋多巴治疗提供了机会。单胺的高亲和力转运体是抗抑郁药物的主要靶点。然而，许多患者的治疗效果欠佳或对治疗无反应。有机阳离子转运体和质膜单胺转运体在调节单胺神经传递中起重要作用，作为治疗药物开发的靶点具有潜在应用价值。不仅要了解单胺在中枢神经系统中作为一个整体是如何相互影响的，还要解决特定核心症状或不同综合征维度（认知障碍、运动迟缓及消极情绪）的病理生理学问题，而不考虑疾病分类，如精神病性、情感性和神经退行性疾病，这样才能产生更好的治疗方法。
