National Institute on Drug Abuse, Bethesda, MD 20892, USA.
J Neurosci. 2012 May 9;32(19):6711-7. doi: 10.1523/JNEUROSCI.0045-12.2012.
Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [(11)C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([(11)C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [(11)C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.
多巴胺 D2 受体与觉醒有关，但它们在与睡眠剥夺相关的警觉度降低中的作用尚不清楚。我们曾表明，睡眠剥夺会降低纹状体中的多巴胺 D2/D3 受体可及性（通过在对照组中使用 PET 和 [(11)C]raclopride 进行测量），但无法确定这是否反映了多巴胺的增加（[(11)C]raclopride 与多巴胺竞争 D2/D3 受体结合）或受体下调。为了澄清这一点，我们比较了在睡眠剥夺和休息睡眠期间，哌甲酯（一种通过阻断多巴胺转运体增加多巴胺的药物）引起的多巴胺增加，假设如果在睡眠剥夺期间确实增加了多巴胺释放，那么哌甲酯的作用会更大。我们在休息睡眠后和 1 个晚上的睡眠剥夺后用 [(11)C]raclopride 扫描了 20 名对照者；两次都在安慰剂和哌甲酯之后。我们证实了与休息睡眠相比，睡眠剥夺会导致腹侧纹状体中 D2/D3 受体的可及性降低（与休息睡眠相比），这与警觉度降低和嗜睡增加有关。然而，哌甲酯引起的多巴胺增加（与安慰剂相比，通过 D2/D3 受体可及性的降低来衡量）在休息睡眠和睡眠剥夺之间没有差异，并且在睡眠剥夺后给予哌甲酯时与警觉度增加和嗜睡减少有关。在经历了 1 个晚上的异相睡眠剥夺的啮齿动物的微透析中也得到了类似的发现。这些发现与睡眠剥夺时腹侧纹状体中 D2/D3 受体的下调一致，这可能导致与睡眠剥夺相关的觉醒度降低，并证实了在人类中，哌甲酯的唤醒作用增强了 D2 受体信号。
