Gehle V M, Erwin V G
Alcohol Research Center and Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver 80262, USA.
Alcohol Clin Exp Res. 2000 May;24(5):579-87.
It has been proposed that development of tolerance to the behavioral effects of ethanol depends on the degree of impairment produced by the drug; that is, more sensitive individuals should develop greater tolerance. Tests of this hypothesis with respect to acute functional tolerance have produced contradictory results. We tested the hypothesis by examining the genetic relationship between initial sensitivity and acute functional tolerance in the LSXSS recombinant inbred mice.
We tested mice for initial sensitivity to the ataxic effects of 1.75 g/kg of ethanol in a stationary dowel balance test by determining blood and brain ethanol concentrations at fall. Acute tolerance to the ataxic effects of ethanol was determined by measuring blood ethanol concentration (BEC) at regain of dowel balance ability after the first injection (BEC1RB) and after a second ethanol injection of 2.0 g/kg (BEC2RB). Acute tolerance was quantified by the difference in ethanol concentration at the two regains of balance (BEC2RB - BEC1RB) or by the difference between the second regain and one of the initial sensitivity measures (BEC2RB - initial sensitivity).
Four different measures of initial sensitivity were taken: two that used BEC values and two that used forebrain or hindbrain ethanol concentrations. We calculated acute tolerance values by using each of these initial sensitivity measures plus BEC2RB. No evidence of a genetic relationship between initial sensitivity and acute tolerance was found, which suggests that these are two independent phenomena with respect to stationary dowel balance.
Three conclusions can be drawn from this work: (1) Orbital sinus BEC at early time points (<5 min postinjection) may or may not accurately reflect brain EC in mice, dependent on genotype; (2) there is no genetic relationship between initial sensitivity and acute tolerance to stationary dowel ataxia in the LSXSS RIs; and (3) sex-specific factors affect low-dose ethanol responses on the stationary dowel.
有人提出，对乙醇行为效应的耐受性发展取决于药物产生的损害程度；也就是说，更敏感的个体应该产生更大的耐受性。关于急性功能耐受性的这一假设检验产生了相互矛盾的结果。我们通过研究 LSXSS 重组近交系小鼠的初始敏感性与急性功能耐受性之间的遗传关系来检验这一假设。
我们通过在固定销平衡试验中测定小鼠跌倒时的血液和脑乙醇浓度，来测试小鼠对 1.75 g/kg 乙醇共济失调效应的初始敏感性。通过测量第一次注射后恢复销平衡能力时的血液乙醇浓度（BEC1RB）以及第二次注射 2.0 g/kg 乙醇后恢复时的血液乙醇浓度（BEC2RB），来确定对乙醇共济失调效应的急性耐受性。急性耐受性通过两次恢复平衡时乙醇浓度的差异（BEC2RB - BEC1RB）或第二次恢复与初始敏感性测量值之一的差异（BEC2RB - 初始敏感性）来量化。
采用了四种不同的初始敏感性测量方法：两种使用 BEC 值，两种使用前脑或后脑乙醇浓度。我们通过使用这些初始敏感性测量方法中的每一种加上 BEC2RB 来计算急性耐受性值。未发现初始敏感性与急性耐受性之间存在遗传关系的证据，这表明就固定销平衡而言，它们是两个独立的现象。
这项工作可以得出三个结论：（1）注射后早期时间点（<5 分钟）的眶窦 BEC 可能准确反映也可能不准确反映小鼠脑中的乙醇浓度，这取决于基因型；（2）在 LSXSS 重组近交系小鼠中，初始敏感性与对固定销共济失调的急性耐受性之间不存在遗传关系；（3）性别特异性因素影响低剂量乙醇对固定销的反应。
