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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

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Abstract

Rationale and objectives

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.

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Acknowledgments

Research was supported by the National Institute on Drug Abuse’s Intramural Research Program. We thank Xingyu Hou for helping with the molecular assays and Brittany Navarre and Anna Stern for helping with the intravenous surgeries. We also thank Dr. Anne E. West (Duke University) for helpful comments on the molecular aspects of our work. The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript.

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  1. Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, 251 Bayview Boulevard, Baltimore, MD, 21224, USA

    Florence R. M. Theberge, Charles L. Pickens, Evan Goldart, Sanya Fanous, Bruce T. Hope, Qing-Rong Liu & Yavin Shaham

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  1. Florence R. M. Theberge
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  2. Charles L. Pickens
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  3. Evan Goldart
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Correspondence to Yavin Shaham.

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Suppl. Fig. 1

(A) Approximate dissection areas for nucleus accumbens and dorsal striatum and (Bregma +1.4 to +2.4) or mPFC (Bregma +2.7 to +3.7) (Paxinos and Watson 2005). (B) Representatives pictures of the Western Blots of MeCP2, BDNF, TrkB, and (phospho)-tyrosine 817 TrkB (pY817TrkB) in nucleus accumbens, dorsal striatum, and medial prefrontal cortex. (PDF 131 kb)

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Theberge, F.R.M., Pickens, C.L., Goldart, E. et al. 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. Psychopharmacology 224, 559–571 (2012). https://doi.org/10.1007/s00213-012-2784-z

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