Wisor J P, Morairty S R, Huynh N T, Steininger T L, Kilduff T S
Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
Neuroscience. 2006 Aug 11;141(1):371-8. doi: 10.1016/j.neuroscience.2006.03.028. Epub 2006 May 11.
Most hypnotic medications currently on the market target some aspect of GABAergic neurotransmission. Although all such compounds increase sleep, these drugs differentially affect the activity of the cerebral cortex as measured by the electroencephalogram. Whereas benzodiazepine medications such as triazolam tend to suppress slow wave activity in the cortex, the GABA(B) ligand gamma-hydroxybutyrate greatly enhances slow wave activity and the non-benzodiazepine, zolpidem, which binds to the omega1 site on the GABA(A) receptor/Cl(-) ionophore complex, is intermediate in this regard. Our previous studies have demonstrated that a small number of genes exhibit increased expression in the cerebral cortex of the mouse and rat during recovery sleep after sleep deprivation: egr-3, fra-2, grp78, grp94, ngfi-b, and nr4a3. Using these genes as a panel of biomarkers associated with sleep, we asked whether hypnotic medications induce similar molecular changes in the rat cerebral cortex to those observed when both sleep continuity and slow wave activity are enhanced during recovery sleep. We find that, although each drug increases the expression of a subset of genes in the panel of biomarkers, no drug fully replicates the molecular changes in the cortex associated with recovery sleep. Furthermore, high levels of slow wave activity in the cortex are correlated with increased expression of fra-2 whereas the expression of grp94 is correlated with body temperature. These results demonstrate that sleep-related changes in gene expression may be affected by physiological covariates of sleep and wakefulness rather than by vigilance state per se.
目前市面上的大多数催眠药物都作用于GABA能神经传递的某些方面。尽管所有这些化合物都能增加睡眠，但通过脑电图测量，这些药物对大脑皮层活动的影响存在差异。像三唑仑这样的苯二氮䓬类药物往往会抑制皮层中的慢波活动，而GABA(B)配体γ-羟基丁酸则会大大增强慢波活动，与GABA(A)受体/Cl(-)离子通道复合物上的ω1位点结合的非苯二氮䓬类药物唑吡坦在这方面则处于中间状态。我们之前的研究表明，在睡眠剥夺后的恢复睡眠期间，小鼠和大鼠大脑皮层中有少数基因的表达会增加：即早反应基因-3（egr-3）、Fos相关抗原2（fra-2）、葡萄糖调节蛋白78（grp78）、葡萄糖调节蛋白94（grp94）、神经生长因子诱导蛋白B（ngfi-b）和核受体亚家族4A成员3（nr4a3）。我们将这些基因作为一组与睡眠相关的生物标志物，探讨催眠药物是否会在大鼠大脑皮层中诱导出与恢复睡眠期间睡眠连续性和慢波活动增强时所观察到的类似分子变化。我们发现，尽管每种药物都会增加生物标志物组中一部分基因的表达，但没有一种药物能完全复制与恢复睡眠相关的皮层分子变化。此外，皮层中高水平的慢波活动与fra-2表达增加相关，而grp94的表达与体温相关。这些结果表明，与睡眠相关的基因表达变化可能受睡眠和觉醒的生理协变量影响，而非仅仅取决于警觉状态本身。
