MECHANISMS THAT UNDERLIE SEX‐LINKED AND GENOTYPICALLY DETERMINED DIFFERENCES IN THE DEPRESSANT ACTIONS OF ALCOHOL *
MECHANISMS THAT UNDERLIE SEX‐LINKED AND GENOTYPICALLY DETERMINED DIFFERENCES IN THE DEPRESSANT ACTIONS OF ALCOHOL *
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酒精抑制作用中性别相关和基因决定差异的机制 *
DOI：
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发表时间：
1976
影响因子：
5.2
通讯作者：
T. N. Yeager
中科院分区：
文献类型：
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作者：
A. C. Collins;M. Lebsack;T. N. Yeager
有几种广义的理论试图解释对镇静催眠剂（例如乙醇）的身体依赖性。大多数理论指出，身体依赖性的发展似乎伴随着中枢神经系统（CNS）对酒精抑制作用的耐受性的获得。这一观察结果表明，解释酒精耐受性的相同神经化学变化也可能解释对这种药物的身体依赖性。几乎所有旨在检验这一假设的研究都利用高剂量乙醇对实验动物进行长期治疗。这种方法有一个主要缺点，即长期高剂量治疗通常会导致动物患有中度至重度营养不良。因此，获得的结果是模棱两可的，因为不能完全保证观察到的任何生化变化都是由乙醇的作用造成的。如果宽容是。事实上，与身体依赖性相关，对酒精表现出较高初始（即第一剂量）耐受性的动物似乎可能会更快地对乙醇产生身体依赖性。如果这是真的，那么识别出最初对酒精的敏感性差异背后的因素可能会为识别与获得性耐受性以及对乙醇的身体依赖性有关的变化提供线索。在此报告的实验中，我们试图确定对酒精的初始敏感性差异背后的机制。我们希望，一旦确定了这些机制，获得性耐受的可能来源也将被揭示。此外，如果获得性耐受性和身体依赖性与同一现象相关的假设是正确的，那么身体依赖性的根本原因可能会更容易被研究，而不会混淆与饮食不足相关的问题。对乙醇敏感性最方便、最容易量化的测量方法之一是服用催眠剂量的这种药物后翻正反射丧失的持续时间（酒精诱导的睡眠时间）。根据先验的基础，两个因素应该主要负责控制酒精引起的睡眠时间的持续时间：中枢神经系统对酒精抑制作用的敏感性和酒精消除的速度。这两个参数似乎都受到基因型的影响。例如。 McClearn 和 Kakihana' 通过对异质小鼠种群进行选择性育种，获得了两个在酒精诱导的睡眠时间持续时间方面存在显着差异的品系。这种差异似乎是由于中枢神经系统对酒精抑制作用的敏感性不同*，导致翻正反射丧失所需剂量的两倍差异证明了这一点，此外，
There are several generalized theories that attempt to explain physical dependence on sedative-hypnotic agents, such as ethanol. Most of these theories note that development of physical dependence appears to be accompanied by the acquisition of central nervous system (CNS) tolerance to the depressant actions of alcohol. This observation has led to the suggestion that the same neurochemical alterations that explain tolerance to alcohol may also explain physical dependence on this agent. Nearly all of the studies designed to test this hypothesis have utilized chronic treatment of experimental animals with high doses of ethanol. This approach has one major disadvantage in that long-term high-dose treatment generally produces an animal that is suffering from moderate to severe malnutrition. The results obtained have therefore been equivocal, because it cannot be stated with complete assurance that any biochemical alterations observed were specifically due to the actions of ethanol. I f tolerance is. indeed, associated with physical dependence, it seems possible that animals that display a higher initial ( k . , first-dose) tolerance to alcohol will become physically dependent on ethanol more rapidly. I f this is true, the identification of factors that underlie differences in initial sensitivity to alcohol may provide clues to the identity of changes that are involved in acquired tolerance and, hopefully, physical dependence on ethanol. In the experiments reported here, we have attempted to ascertain the mechanisms that underlie differences in initial sensitivity to alcohol. It is our hope that, once these mechanisms have been identified, a likely source of acquired tolerance will also have been revealed. In addition, if the hypothesis that acquired tolerance and physical dependence are related to the same phenomena is correct, the underlying causes of physical dependence may be more easily studied without confounding problems associated with dietary deficiencies. One of the most convenient and easily quantified measures of sensitivity to ethanol is the duration of loss of righting reflex (alcohol-induced sleep time) after the administration of a hypnotic dose of this agent. On an a priori basis, two factors should be primarily responsible for controlling the duration of alcohol-induced sleep time: CNS sensitivity to the depressant actions of alcohol and rate of alcohol elimination. Both of these parameters seem to be influenced by genotype. For example. McClearn and Kakihana' have obtained, by selective breeding from a heterogeneous stock of mice, two lines that differ substantially in duration of alcoholinduced sleep time. This difference appears to be due to differing CNS sensitivities to the depressant actions of alcohol,* as evidenced by a twofold difference in the dose required to cause loss of the righting reflex, in addition to a substantial difference in