National Institute on Drug Dependence, Peking University, Beijing, China.
J Neurochem. 2010 Oct;115(2):353-62. doi: 10.1111/j.1471-4159.2010.06941.x. Epub 2010 Aug 25.
Protracted opiate withdrawal can extend for months of disrupted hormonal circadian rhythms. We examined rodent behaviors and these circadian disturbances in hormone and peptide levels as well as brain clock gene expression during 60 days of protracted withdrawal. Our behavioral tests included open field, elevated plus maze, and sucrose preference tests at 36 h, 10, 30, and 60 days after stopping chronic morphine. At these four assessment points, we collected samples every 4 h for 24 h to examine circadian rhythms in blood hormone and peptide levels and brain expression of rPER1, rPER2, and rPER3 clock genes. Decreased locomotor activity and elevated adrenocorticotropic hormone and melatonin levels persisted for 2 months after morphine withdrawal, but corticosterone was elevated only at 36 h and 10 days after withdrawal. Orexin levels were high at 36 h after withdrawal, but then reversed during protracted withdrawal to abnormally low levels. Beta-endorphin (β-EP) levels showed no differences from normal. However, circadian rhythms were blunted for all of these hormones. Corticosterone, adrenocorticotropic hormone, and orexin blunting persisted at least for 60 days. The blunted circadian rhythm of β-EP and melatonin recovered by day 60, but the peak phase of β-EP was delayed about 8 h. Blunted circadian rhythms and reduced expression of rPER1, rPER2, and rPER3 persisted at least for 60 days in the suprachiasmatic nucleus, prefrontal cortex, nucleus accumbens core, central nucleus of the amygdala, Hippocampus, and ventral tegmental area. Circadian rhythms of rPER1 in the nucleus accumbens shell and basolateral nucleus of the amygdala and of rPER2 in the central nucleus of the amygdala were reversed. Disrupted circadian rhythms of rPER1, rPER 2, and rPER3 expression in reward-related brain circuits and blunted circadian rhythms in peripheral hormones and peptides may play a role in protracted opiate withdrawal and contribute to relapse.
阿片类药物戒断时间延长可导致数月的激素昼夜节律紊乱。我们研究了 60 天戒断期间啮齿动物的行为以及激素和肽水平的这些昼夜节律紊乱和大脑时钟基因表达。我们的行为测试包括旷场实验、高架十字迷宫和蔗糖偏好实验，分别在停止慢性吗啡后 36 小时、10 天、30 天和 60 天进行。在这四个评估点，我们每 4 小时收集一次样本，持续 24 小时，以检查血液激素和肽水平以及大脑 rPER1、rPER2 和 rPER3 时钟基因的昼夜节律。在吗啡戒断后 2 个月，运动活动减少，促肾上腺皮质激素和褪黑素水平升高，但皮质酮仅在戒断后 36 小时和 10 天升高。食欲素水平在戒断后 36 小时升高，但在戒断延长期间逆转至异常低水平。β-内啡肽 (β-EP) 水平与正常水平无差异。然而，所有这些激素的昼夜节律都减弱了。皮质酮、促肾上腺皮质激素和食欲素的减弱至少持续 60 天。β-EP 和褪黑素的昼夜节律恢复，但β-EP 的峰值相位延迟约 8 小时。至少在 60 天内，rPER1、rPER2 和 rPER3 的昼夜节律减弱和表达减少持续存在于视交叉上核、前额叶皮层、伏隔核核心、杏仁核中央核、海马体和腹侧被盖区。rPER1 在伏隔核壳和杏仁核基底外侧核以及 rPER2 在杏仁核中央核的昼夜节律逆转。奖赏相关脑回路中 rPER1、rPER2 和 rPER3 表达的昼夜节律紊乱和外周激素和肽的昼夜节律减弱可能在阿片类药物戒断延长中起作用，并导致复发。
