Evrard Alexis, Barden Nicolas, Hamon Michel, Adrien Joëlle
UMR 677 INSERM-UPMC, Neuropsychopharmacologie, CHUPitié-Salpêtrière, Paris, France.
Sleep. 2006 Jan;29(1):31-6. doi: 10.1093/sleep/29.1.31.
Sleep deprivation for one night induces mood improvement in depressed patients, an action that probably involves the serotonergic (5-HT) system. In animals, sleep deprivation and pharmacologic treatment with antidepressants exert similar effects on 5-HT neurotransmission, notably functional desensitization of 5-HT1A autoreceptors located on 5-HT neurons in the dorsal raphe nucleus (DRN). However, in stressful conditions, corticosterone can also induce a desensitization of these autoreceptors.
To investigate the mechanisms of this adaptation during sleep deprivation and the possible involvement of corticosterone, we studied the effects of an 18-hour sleep deprivation, by forced locomotion, on 5-HT1A receptor-mediated firing response of DRN 5-HT neurons in transgenic mice with impaired glucocorticoid-receptor expression (GR-i) and in wild-type animals. We also examined the effects of chronic treatment with the antidepressant drug fluoxetine in the same paradigm.
In both wild-type and GR-i mice, the 18-hour sleep deprivation or fluoxetine treatment had no effect on the spontaneous firing of 5-HT neurons recorded under anesthesia. However, sleep deprivation decreased the potency of the 5-HT1A agonist 8-OH-DPAT to inhibit 5-HT neuronal firing in wild-type mice, whereas it had no effect in GR-i animals. Conversely, after chronic fluoxetine treatment, the induced reduction of this 5-HT1A autoreceptor-driven response was of larger amplitude in GR-i than in wild-type mice.
These data suggest that glucocorticoid-receptor activation by corticosterone participates in the antidepressant-like adaptive changes in 5-HT1A autoreceptors in sleep-deprived mice. On the other hand, GR-i animals exhibited enhanced 5-HT1A autoreceptor desensitization induced by fluoxetine, in line with data in other animal models of depression.
一晚的睡眠剥夺可使抑郁症患者的情绪得到改善，这一作用可能涉及血清素能（5-HT）系统。在动物中，睡眠剥夺和用抗抑郁药进行药物治疗对5-HT神经传递有相似的作用，特别是对位于中缝背核（DRN）的5-HT神经元上的5-HT1A自身受体的功能脱敏。然而，在应激条件下，皮质酮也可诱导这些自身受体的脱敏。
为了研究睡眠剥夺期间这种适应性的机制以及皮质酮可能的参与情况，我们通过强迫运动研究了18小时睡眠剥夺对糖皮质激素受体表达受损的转基因小鼠（GR-i）和野生型动物中DRN 5-HT神经元的5-HT1A受体介导的放电反应的影响。我们还在相同范式下研究了抗抑郁药氟西汀的慢性治疗效果。
在野生型和GR-i小鼠中，18小时的睡眠剥夺或氟西汀治疗对麻醉下记录的5-HT神经元的自发放电均无影响。然而，睡眠剥夺降低了5-HT1A激动剂8-OH-DPAT抑制野生型小鼠中5-HT神经元放电的效力，而对GR-i动物没有影响。相反，在慢性氟西汀治疗后，GR-i小鼠中这种由5-HT1A自身受体驱动的反应的诱导降低幅度比野生型小鼠更大。
这些数据表明，皮质酮激活糖皮质激素受体参与了睡眠剥夺小鼠中5-HT1A自身受体的抗抑郁样适应性变化。另一方面，GR-i动物表现出由氟西汀诱导的增强的5-HT1A自身受体脱敏，这与其他抑郁症动物模型中的数据一致。
