Alterations in monoamine-containing neuronal function due to administration of antidepressants repeatedly to rats.
Alterations in monoamine-containing neuronal function due to administration of antidepressants repeatedly to rats.
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大鼠反复服用抗抑郁药导致含单胺神经元功能的改变。
DOI：
10.1111/j.1600-0773.1985.tb02496.x
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Sills,M
中科院分区：
文献类型：
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作者：
Frazer,A;Lucki,I;Sills,M
在过去的十年里，人们对研究抗抑郁治疗的药理作用的兴趣激增。这些研究部分受到技术进步的刺激，特别是用于测量神经递质受体的配体结合技术的出现（Miledi等人，Nature 1971，229：554; Changeux等人，分子药理学1971，- 7：538;参见霍夫曼和莱夫科维茨，《药理学年鉴》。毒理学. 1980，20：581）。其他分析方面的进展，如用于测量单胺及其代谢物的高效液相色谱技术的发展，也促进了药物对中枢单胺能系统影响的研究。此外，20世纪70年代中期出现的某些实验结果引起了对抗抑郁药可能起作用的方式的概念性重新评估。在此之前，几乎所有的研究都集中在抗抑郁药的“突触前”效应（例如，对单胺浓度，营业额，摄取等的影响）。在体外或在其急性施用后观察到。然而，当显示抗抑郁药治疗的重复给药以意想不到的方式改变去甲肾上腺素能反应时（弗雷泽et al.，Neuropharmacol. 1974年，13：1131; Vetulani和Sulser，Nature 1975，-257：495），它将注意力转移到”突触后”神经元和在重复施用抗抑郁药后观察到的药理学作用。本文的目的不是对这一大量数据进行全面审查。本卷中的许多其他文章都说明了这些材料。相反，我们将回顾我们自己的小组在这一领域所做的一些工作，特别强调我们试图确定重复给予大鼠抗抑郁药引起的单胺受体变化是否有生理或行为后果。β-肾上腺素能受体和反应在继续之前，有一点值得讨论。在反复给药后检查抗抑郁药治疗效果的最常见原因是，在开始治疗和临床改善之间有2-3周的滞后期。如果这是真的，则可以推断，显示相似时程的药理学效应可能比动物抗抑郁药给药后立即发生的效应与临床疗效更相关。许多研究人员现在发现了各种”延迟”效应，并推测这些效应可以解释药物的临床疗效。我们确实做到了这一点（Heydorn等人，J. Pharmacol. Exp.心理医生1982，222：534;参见弗雷泽和Lucki，在：典型和非典型抗抑郁药：分子机制中，Raven Press，1982，pp. 69-90）。但是，在治疗开始和临床改善开始之间是否有一个滞后期？如果有，支持滞后期存在的证据是最小的，部分原因是难以设计一项研究来回答这个问题。文献综述显示，在许多研究中：1）患者在研究的前两周继续接受现在可能被认为是剂量不足的三环类药物; 2）使用的评级量表可能不够敏感，无法检测早期细微的改善迹象; 3）在治疗一周前很少对患者反应进行评价。此外，许多抑郁症患者对安慰剂的良好建立的初始反应（参见Klerman和科尔，Pharmacol. Rev. 1965，c：101）是检测早期药理学诱导的改善的任何尝试中的重要混杂物。可能是临床反应
The past decade has seen a virtual explosion of interest in research examining the pharmacological effects of antidepressant treatments. Such studies were stimulated in part by technical advances, particularly the advent of ligand binding techniques for measuring neurotransmitter receptors (Miledi et al., Nature 1971, 229: 554; Changeux et al., Mol Pharmacol. 1971,- 7: 538; see Hoffman and Lefkowitz, Ann. Rev. Pharmacol. Toxicol. 1980, 20: 581). Other analytical advances, like the development of high performanceliquid chromatographic techniques for the measurement of monoamines and their metabolites, also facilitated the study of drug effects on central monoaminergic systems. In addition, certain experimental results that appeared in the mid 1970's caused a conceptual re-evaluation of the manner in which antidepressants might act. Prior to that time, almost all research had focused on" pre-synaptic" effects of antidepressants (eg, effects on monoamine concentrations, turnover, uptake, etc.) observed either in vitro or after their acute administration. When it was shown, though, that repeated administration of antidepressant treatments changed noradrenergic responses in an unexpected manner (Frazer et al., Neuropharmacol. 1974, 13: 1131; Vetulani and Sulser, Nature 1975,-257: 495), it shifted attentiontowards the" post-synaptic" neuron and towards pharmacological effects observed after repeated administration of antidepressants. The purpose of this article is not to provide a comprehensive review of this large body of data. Many of the other articles in this volume illustrate this material. Rather, we will review some of the work done by our own group in this area, with particular emphasis on our efforts to try to determine if there are physiological or behavioral consequences of the changes in monoamine receptors caused by repeated administration of antidepressants to rats.I. Beta-Adrenergic Receptors and Responses Before proceeding, it is worthwhile discussing one point. The reason most often given-for examining the effects of antidepressant-treatments after their repeated administration is that there is a lag period, of 2-3 weeks, between initiation of therapy and clinical improvement. If this is true, it was reasoned that pharmacological effects showing a similar time course might be more related to clinical efficacy than effects occurring immediately following the administration of antidepressants to animals. Many investigators have now found a variety of" delayed" effects and speculate that such effects could account for the clinical efficacy of the drugs. We have certainly done this (Heydorn et al., J. Pharmacol. Exp. Therap. 1982, 222: 534; see Frazer and Lucki, In: Typical and Atypical Antidepressants: Molecular Mechanisms, Raven Press, 1982, pp. 69-90). But is there a lag period between the beginning of therapy and the onset of clinical improvement? If there is, the evidence to support the existence of a lag period is minimal due in part to the difficulty in designing a study to answer the question. A review of the literature shows that in many studies: 1) patients were kept on what might now be considered inadequate doses of tricyclics for the first two weeks of the study; 2) rating scales were used that may not have been sufficiently sensitive to detect early subtle signs of improvement; and 3) evaluation of patient response was rarely done before one week of treatment. In addition, the well-established initial response of many depressed patients to placebo (see Klerman and Cole, Pharmacol. Rev. 1965, c: lOl) is an important confound in any attempt to detect early pharmacologically-induced improvement. Perhaps clinical response