Silveri M M, Spear L P
Department of Psychiatry, Harvard Medical School and Cognitive Neuroimaging and Neuropsychology Laboratory, Brain Imaging Center, McLean Hospital, Belmont, Massachusetts 02478, USA.
Alcohol Clin Exp Res. 2004 Jun;28(6):884-94. doi: 10.1097/01.alc.0000128221.68382.ba.
Sensitivity to several ethanol effects increases during ontogeny, perhaps in part because of a notable decline in acute tolerance. In contrast, rapid tolerance to ethanol-induced sedation emerges slowly during ontogeny. This study tested the hypothesis that ontogenetic differences in glutamate and/or gamma-aminobutyric acid systems influence tolerance expression.
Sprague-Dawley rats at postnatal day (P)26 or P70 received (+)MK-801, muscimol, or saline before ethanol (3.5 or 4.5 g/kg) or saline on day 1 and ethanol only on day 2. Loss of and time to regain the righting reflex and blood alcohol levels at recovery were recorded. The presence of acute tolerance was indicated as a positive slope of the linear regression of blood alcohol levels at recovery versus ethanol dose. Rapid tolerance was estimated on day 2 by comparing animals given ethanol only on day 2 with those given ethanol on both days.
Acute tolerance on day 1 only was observed at P26; this was disrupted by (+)MK-801 but not muscimol. Evidence for acute tolerance also emerged in adults on day 2. Whereas both drugs increased ethanol sedation at both ages, they did not facilitate ontogenetic expression of rapid tolerance: rapid tolerance was not evident at P26 regardless of pretreatment when indexed in terms of recovery time.
These data provide further evidence for an ontogenetic dissociation in the expression of acute and rapid tolerance to ethanol-induced sedation. Pharmacological attenuation of the expression of acute tolerance was sufficient but not necessary to delay recovery of righting after ethanol. The greater propensity of young animals to develop acute tolerance, seemingly modulated in part by NMDA receptors, may contribute to their relative resistance to ethanol, although other factors, including pharmacokinetic factors, also contribute to their more rapid recovery from ethanol sedation.
在个体发育过程中，对多种乙醇效应的敏感性会增加，这可能部分归因于急性耐受性的显著下降。相比之下，对乙醇诱导的镇静作用的快速耐受性在个体发育过程中出现得较慢。本研究检验了谷氨酸和/或γ-氨基丁酸系统的个体发育差异影响耐受性表达的假说。
出生后第（P）26天或第70天的Sprague-Dawley大鼠在第1天接受（+）MK-801、蝇蕈醇或生理盐水，然后给予乙醇（3.5或4.5 g/kg）或生理盐水，第2天仅给予乙醇。记录翻正反射消失和恢复的时间以及恢复时的血醇水平。恢复时血醇水平与乙醇剂量的线性回归呈正斜率表明存在急性耐受性。通过比较仅在第2天给予乙醇的动物和两天均给予乙醇的动物，在第2天评估快速耐受性。
仅在P26时观察到第1天的急性耐受性；这被（+）MK-801破坏，但未被蝇蕈醇破坏。在第2天，成年大鼠也出现了急性耐受性的证据。尽管两种药物在两个年龄段均增加了乙醇诱导的镇静作用，但它们并未促进快速耐受性的个体发育表达：无论预处理如何，以恢复时间为指标时，P26时均未出现明显的快速耐受性。
这些数据为乙醇诱导的镇静作用的急性耐受性和快速耐受性表达的个体发育解离提供了进一步的证据。急性耐受性表达的药理学减弱足以但并非延迟乙醇后翻正恢复所必需。幼小动物形成急性耐受性的倾向更大，似乎部分受N-甲基-D-天冬氨酸受体调节，这可能导致它们对乙醇的相对抗性，尽管其他因素，包括药代动力学因素，也有助于它们从乙醇镇静中更快恢复。
