Circadian alteration in neurobiology during protracted opiate withdrawal in rats.
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.
Li
Su-xia
SX
National Institute on Drug Dependence, Peking University, Beijing, China. lisuxia70@163.com
Liu
Li-jing
LJ
Jiang
Wen-gao
WG
Sun
Li-li
LL
Zhou
Shuang-jiang
SJ
Le Foll
Bernard
B
Zhang
Xiang Yang
XY
Kosten
Thomas R
TR
Lu
Lin
L
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008550:Melatonin / Q000097:blood; D009020:Morphine / Q000009:adverse effects*; D009446:Neurobiology; D009479:Neuropeptides / Q000097:blood; D000068797:Orexins; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D001615:beta-Endorphin / Q000097:blood
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D056950:Period Circadian Proteins; D001615:beta-Endorphin; D009020:Morphine; D000324:Adrenocorticotropic Hormone; D008550:Melatonin