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首页> 外文期刊>Neuropharmacology >Endogenous gamma-aminobutyric acid (GABA)(A) receptor active neurosteroids and the sedative/hypnotic action of gamma-hydroxybutyric acid (GHB): A study in GHB-S (sensitive) and GHB-R (resistant) rat lines.
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Endogenous gamma-aminobutyric acid (GABA)(A) receptor active neurosteroids and the sedative/hypnotic action of gamma-hydroxybutyric acid (GHB): A study in GHB-S (sensitive) and GHB-R (resistant) rat lines.

机译：内源性γ-氨基丁酸（GABA）（A）受体活性神经甾体和γ-羟基丁酸（GHB）的镇静/催眠作用：在GHB-S（敏感）和GHB-R（耐药）大鼠系中进行的研究。

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In the rat brain, gamma-hydroxybutyric-acid (GHB) increases the concentrations of 3alpha-hydroxy,5alpha-pregnan-20-one (allopregnanolone, 3alpha,5alpha-THP) and 3alpha,21-dihydroxy,5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone/3alpha,5alphaTHDOC), two neurosteroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors. This study was aimed at assessing whether neurosteroids play a role in GHB-induced loss of righting reflex (LORR). Basal and GHB-stimulated brain concentrations of endogenous 3alpha,5alpha-THP and 3alpha,5alpha-THDOC were analyzed in two rat lines, GHB-sensitive (GHB-S) and GHB-resistant (GHB-R), selectively bred for opposite sensitivity to GHB-induced sedation/hypnosis. Basal neurosteroid concentrations were similar in brain cortex of the two rat lines. However, in male GHB-S rats, administration of GHB (1000 mg/kg, i.p., 30 min) increased brain cortical concentrations of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC 7- and 2.5-fold, respectively, whilst male GHB-R animals displayed only a 4- and 2-fold increase, respectively. In GHB-S rats this increase lasted up to 90 min and declined 180 min following GHB administration, a time course that matches LORR onset and duration. In contrast, in GHB-R rats, which failed to show GHB-induced LORR, brain cortical 3alpha,5alpha-THP and 3alpha,5alpha-THDOC had returned to control values within 90 min. At onset of LORR, a similar increase in brain cortical levels of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC (2-3-fold) was observed in GHB-S female rats and in the few female GHB-R rats that lost the righting reflex after GHB administration, but not in female GHB-R rats failing to show LORR. Sub-hypnotic doses (7.5 and 12.5 mg/kg, i.p.) of pregnanolone, administered 10 min before GHB, dose-dependently facilitated the expression of GHB-induced LORR in GHB-R male rats. These results suggest that the GHB-induced increases of brain 3alpha,5alpha-THP and 3alpha,5alpha-THDOC concentrations are implicated in the eliciting of the sedative/hypnotic action of GHB.
机译：在大鼠大脑中，γ-羟基丁酸（GHB）增加了3α-羟基，5α-pregnan-20-one（allopregnanolone，3alpha，5alpha-THP）和3alpha，21-dihydroxy，5alpha-pregnan-20-一种（allotetrahydrodeoxycorticosterone / 3alpha，5alphaTHDOC），两种神经固醇充当γ-氨基丁酸（GABA）（A）受体的正变构调节剂。这项研究旨在评估神经固醇是否在GHB诱导的扶正反射丧失（LORR）中起作用。在两个大鼠品系GHB敏感（GHB-S）和GHB抵抗（GHB-R）中分析了基础和GHB刺激的内源性3alpha，5alpha-THP和3alpha，5alpha-THDOC的脑浓度，并选择了相反的敏感性进行饲养对GHB引起的镇静/催眠作用。两条大鼠系的大脑皮层中基础神经甾体浓度相似。但是，在雄性GHB-S大鼠中，给予GHB（1000 mg / kg，腹腔注射，30分钟），可使大脑皮层中3alpha，5alpha-THP和3alpha，5alpha-THDOC的浓度分别增加7倍和2.5倍。 GHB-R动物分别仅表现出4倍和2倍的增长。在GHB-S大鼠中，这种增加持续了90分钟，而在施用GHB后下降了180分钟，这一时程与LORR发作和持续时间相匹配。相反，在未能显示GHB诱导的LORR的GHB-R大鼠中，大脑皮层3alpha，5alpha-THP和3alpha，5alpha-THDOC在90分钟内恢复为对照值。在LORR发作时，在GHB-S雌性大鼠和少数雌性GHB-R大鼠中观察到类似的3alpha，5alpha-THP和3alpha，5alpha-THDOC大脑皮质水平升高（2-3倍） GHB给药后的扶正反射，但未显示LORR的雌性GHB-R大鼠则没有。在GHB前10分钟给予亚催眠剂量的孕烯醇酮（7.5和12.5 mg / kg，腹腔注射）剂量依赖性地促进GHB-R雄性大鼠中GHB诱导的LORR的表达。这些结果表明，GHB诱导的大脑3alpha，5alpha-THP和3alpha，5alpha-THDOC浓度增加与引起GHB的镇静/催眠作用有关。

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