Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving.
OBJECTIVE
Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence.


METHODS
We trained rats to self-administer heroin or saline for 9-10 days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone's (0-1.0 mg/kg) effect on extinction responding after 1 and 15 days.


RESULTS
Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day 11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day 1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1 day.


CONCLUSIONS
Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving.
Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Florence R M
FR
Theberge
Charles L
CL
Pickens
Evan
E
Goldart
Sanya
S
Fanous
Bruce T
BT
Hope
Qing-Rong
QR
Liu
Yavin
Y
Shaham
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D003463:Cues; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000523:psychology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012646:Self Administration; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D009292:Narcotic Antagonists; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D009270:Naloxone; D003932:Heroin; D020813:Receptor, trkB