Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine.
BACKGROUND
Opiate abuse is a chronic relapsing disorder, and maintaining prolonged abstinence remains a major challenge. Protracted abstinence is characterized by lowered mood, and clinical studies show elevated comorbidity between addiction and depressive disorders. At present, their relationship remains unclear and has been little studied in animal models. Here we investigated emotional alterations during protracted abstinence, in mice with a history of chronic morphine exposure.


METHODS
C57BL6J mice were exposed to a chronic intermittent escalating morphine regimen (20-100 mg/kg). Physical dependence (naloxone-precipitated withdrawal), despair-related behaviors (tail suspension test), and social behaviors were examined after 1 or 4 weeks of abstinence. Stress hormones and forebrain bioamine levels were analyzed at the end of morphine regimen and after 4 weeks of abstinence. Finally, we examined the effects of chronic fluoxetine during abstinence on morphine-induced behavioral deficits.


RESULTS
Acute naloxone-induced withdrawal was clearly measurable after 1 week, and became undetectable after 4 weeks. In contrast, social and despair-related behaviors were unchanged after 1 week, but low sociability and despair-like behavior became significant after 4 weeks. Chronic morphine regimen increased both corticosterone levels and forebrain serotonin turnover, but only serotonergic activity in the dorsal raphe remained impaired after 4 weeks. Remarkably, chronic fluoxetine prevented depressive-like behavioral deficits in 4-week abstinent mice.


CONCLUSIONS
During protracted abstinence, the immediate consequences of morphine exposure attenuate, whereas fluoxetine-sensitive emotional alterations strengthen with time. Our study establishes a direct link between morphine abstinence and depressive-like symptoms and strongly suggests that serotonin dysfunction represents a main mechanism contributing to mood disorders in opiate abstinence.
Goeldner
Celia
C
Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch, France.
Lutz
Pierre-Eric
PE
Darcq
Emmanuel
E
Halter
Thomas
T
Clesse
Daniel
D
Ouagazzal
Abdel-Mouttalib
AM
Kieffer
Brigitte L
BL
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004644:Emotions / Q000187:drug effects*; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D009021:Morphine Dependence / Q000097:blood / Q000523:psychology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012919:Social Behavior; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D013997:Time Factors
D005473:Fluoxetine; D012701:Serotonin; D009020:Morphine; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone