Van Sassenbroeck Diederik K, De Paepe Peter, Belpaire Frans M, Boon Paul A, Buylaert Walter A
Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium.
J Pharm Pharmacol. 2003 May;55(5):609-15. doi: 10.1211/002235703765344513.
Tolerance to gamma-hydroxybutyrate (GHB) has been suggested in illicit users and has been described for the hypnotic effect in the rat. The aim of this study was to investigate whether tolerance is also observed for the EEG effect, and whether the EEG can give insight into the pharmacodynamic aspects of GHB tolerance. In three series of experiments, rats were pre-treated with either the GHB precursor gamma-butyrolactone (GBL) or saline intraperitoneally twice daily. In the first series, a reduction in sleeping time was observed in the GBL pre-treated rats compared with controls. In the second series, a fast infusion of GHB (300 mg kg(-1) over 5 min) was given after 10 days pre-treatment. The GHB plasma concentration-time curves showed a slightly faster decrease in GHB concentration in the GBL pre-treated rats, suggesting a small induction of the GHB metabolism (V(max) = 2882 +/- 457 microg min(-1) kg(-1) vs 2205 +/- 315 microg min(-1) kg(-1), P < 0.01). In contrast to controls, GBL pre-treated rats did not lose righting reflex. In the third series, a slow infusion of 480 mg kg(-1) h(-1) was given after 7 days pre-treatment, which allowed fitting a sigmoid E(max) model to the EEG amplitude versus GHB plasma concentration curve. This showed reduced end-organ sensitivity to GHB in the GBL pre-treated rats (EC50 (concentration required to obtain 50% depression of the baseline effect) = 653+/- 183 microg mL(-1) vs 323 +/- 68 microg mL(-1), P < 0.001). In conclusion, chronic pre-treatment with gamma-butyrolactone in the rat results in a reduced sleeping time and this tolerance is reflected by the EEG. This can mainly be explained by reduced end-organ sensitivity.
非法使用者中已表明存在对γ-羟基丁酸（GHB）的耐受性，并且在大鼠中已描述了对催眠作用的耐受性。本研究的目的是调查是否也观察到对脑电图（EEG）效应的耐受性，以及EEG是否能深入了解GHB耐受性的药效学方面。在三个系列的实验中，大鼠每天经腹腔注射GHB前体γ-丁内酯（GBL）或生理盐水两次进行预处理。在第一个系列中，与对照组相比，GBL预处理的大鼠睡眠时间减少。在第二个系列中，预处理10天后快速输注GHB（5分钟内300mg/kg）。GHB血浆浓度-时间曲线显示GBL预处理的大鼠中GHB浓度下降略快，表明GHB代谢有小幅度诱导（Vmax = 2882±457μg·min-1·kg-1对2205±315μg·min-1·kg-1，P<0.01）。与对照组不同，GBL预处理的大鼠没有失去翻正反射。在第三个系列中，预处理7天后缓慢输注480mg·kg-1·h-1，这使得能够将S形E(max)模型拟合到EEG振幅与GHB血浆浓度曲线上。这表明GBL预处理的大鼠终末器官对GHB的敏感性降低（EC50（获得基线效应50%抑制所需的浓度）= 653±183μg/mL对323±68μg/mL，P<0.001）。总之，大鼠长期用γ-丁内酯预处理会导致睡眠时间减少，这种耐受性通过EEG得以体现。这主要可通过终末器官敏感性降低来解释。
