title: Persistent increases in rat hypothalamic POMC gene expression following chronic withdrawal from chronic "binge" pattern escalating-dose, but not steady-dose, cocaine.
abstract: Recent research suggests an involvement of pro-opiomelanocortin (POMC) gene products (e.g., beta-endorphin) in modulating cocaine-induced reward and addiction-like behaviors in rodents. In this study, we investigated whether chronic "binge" cocaine and its withdrawal altered POMC gene expression in the brain of rats. Male Fischer rats were treated with two different chronic (14-day) "binge" pattern cocaine administration regimens (three injections at 1-h intervals, i.p.): steady-dose (45mg/kg/day) and escalating-dose (90mg/kg on the last day). Although there was no POMC mRNA alteration after chronic steady-dose cocaine, a significant decrease in POMC mRNA levels in the hypothalamus was found after chronic escalating-dose cocaine. In contrast, after acute (1-day) withdrawal from chronic "binge" escalating-dose regimen, but not steady-dose regimen, there were increased hypothalamic POMC mRNA levels that persisted into 14days of protracted withdrawal. To study the role of the endogenous opioid systems in the cocaine withdrawal effects, we administered a single naloxone injection (1mg/kg) that caused elevated POMC mRNA levels observed 24h later in cocaine naïve rats, but it did not lead to further increases in cocaine-withdrawn rats. Our results suggest that during withdrawal from chronic "binge" escalating-dose cocaine: (1) there was a persistent increase in hypothalamic POMC gene expression; and (2) hyposensitivity of the POMC gene expression to naloxone indicates altered opioidergic tone at or above the hypothalamic level.
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: yan.zhou@rockefeller.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011916:Rats, Inbred F344; D012055:Reinforcement Schedule; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D012333:RNA, Messenger; D009270:Naloxone; D011333:Pro-Opiomelanocortin; D003042:Cocaine; D003345:Corticosterone
keywords: POMC; chronic “binge” cocaine; cocaine withdrawal; escalating-dose; hypothalamus; steady-dose