Neurobiology of lithium: an update.
Neurobiology of lithium: an update.
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发表时间：
1998-07
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通讯作者：
R. Lenox;Robert K. McNamara;R. Papke;H. Manji
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作者：
R. Lenox;Robert K. McNamara;R. Papke;H. Manji
锂仍然是治疗急性躁狂症和预防性管理躁狂抑郁症的一线方法，但潜在的神经生物学机制尚未确定。在本文中，我们严格审查了锂在大脑中作用的临床前和临床证据，并提出了可能对未来研究最有成效的领域，即，膜转运系统、神经递质受体调节、第二信使产生系统、蛋白激酶C（PKC）调节和基因表达。在其实验设计中，临床前研究通常由于相对缺乏对治疗浓度、急性与慢性暴露以及缺乏足够的阳离子和/或精神控制等问题的关注而危及其研究的生理相关性。未来的研究应该考虑锂的预防效果，突然停药后复发躁狂的风险较高，锂稳定与单相障碍相关的复发性抑郁症的能力，以及在抗抑郁药存在的情况下锂治疗难治性重度抑郁症的疗效。在过去的几年里，对锂在大脑中受体介导的磷酸肌醇信号传导中的作用的研究已经开辟了启发性的研究路线，这些研究源于锂对肌醇单磷酸酶的非竞争性抑制。随后的研究涉及调节肌醇转运，PKC同工酶和活性，和表达的主要PKC底物MARCKS（豆蔻酰丙氨酸丰富的C-激酶底物）提供了潜在的途径，了解复杂的行动，长期锂在大脑中。这些研究将使我们更好地了解锂的神经解剖学作用部位，并与正在进行的临床研究一起使用脑成像技术对躁狂抑郁症患者进行更全面的了解这种疾病的病理生理学。
Lithium remains a first-line approach for the treatment of acute mania and the prophylactic management of manic-depressive illness, yet the underlying neurobiological mechanisms remain as yet undefined. In this paper we critically examine the accumulated preclinical and clinical evidence for the action of lithium in the brain and suggest areas that may be most productive for future investigation, i.e., membrane transport systems, neurotransmitter receptor regulation, second messenger generating systems, protein kinase C (PKC) regulation, and gene expression. In their experimental design, preclinical investigations have often jeopardized the physiologic relevance of their studies by a relative lack of attention to issues such as therapeutic concentrations, acute versus chronic exposure, and a lack of adequate cation and/or psychotropic controls. Future studies should account for the established prophylactic efficacy of lithium, the higher risk for relapse into mania after abrupt discontinuation, the ability of lithium to stabilize recurrent depression associated with unipolar disorder, and the efficacy of lithium in the treatment of refractory major depressive disorder in the presence of an antidepressant. Studies of the action of lithium in receptor mediated phosphoinositide signaling in the brain over the past several years have opened up heuristic lines of investigation that stem from lithium's uncompetitive inhibition of the enzyme inositol monophosphatase. Subsequent studies involving regulation of inositol transport, PKC isozymes and activity, and the expression of the major PKC substrate MARCKS (myristoylated alanine-rich C-kinase substrate) have offered potential avenues for understanding the complexity of the action of long-term lithium in the brain. These studies will offer us a better understanding of the neuroanatomical sites of action of lithium and together with ongoing clinical investigations using brain imaging in patients with manic-depressive illness a more complete understanding of the pathophysiology of this disease.