Abstract
BackgroundCocaine exposure has been reported to alter central μ-opioid receptor (MOR) expression in vivo. The present study employed an in vitro cellular model to explore possible mechanisms that may be involved in this action of cocaine.MethodsTo assess the effects of cocaine on MOR levels, two treatment regimens were tested in PC12 cells: single continuous or multiple intermittent. MOR protein levels were assessed by western blot analysis and quantitative PCR was used to determine relative MOR mRNA expression levels. To evaluate the role of nitric oxide (NO) and histone acetylation in cocaine-induced MOR expression, cells were pre-treated with the NO synthase inhibitor Nω-nitro-L-arginine methylester (L-NAME) or the non-selective histone acetyltransferase inhibitor curcumin.ResultsBoth cocaine treatment regimens significantly increased MOR protein levels and protein stability, but only multiple intermittent treatments increased MOR mRNA levels as well as c-fos mRNA levels and activator protein 1 binding activity. Both regimens increased NO production, and pre-treatment with L-NAME prevented cocaine-induced increases in MOR protein and mRNA levels. Single and multiple cocaine treatment regimens inhibited histone deacetylase activity, and pre-treatment with curcumin prevented cocaine-induced up-regulation of MOR protein expression.ConclusionsIn the PC12 cell model, both NO and histone deacetylase activity regulate cocaine-induced MOR expression at both the transcriptional and post-transcriptional levels. Based on these novel findings, it is hypothesized that epigenetic mechanisms are implicated in cocaine’s action on MOR expression in neurons.
Highlights
Cocaine exposure has been reported to alter central μ-opioid receptor (MOR) expression in vivo
Endogenous opioid systems are involved in several aspects of cocaine addiction [1,2,3,4,5], and several studies have indicated that cocaine increases μ-opioid receptor (MOR) mRNA and peptide expression [6,7,8,9,10,11] in regions of the brain known to regulate incentive motivation and stress reactivity [12,13,14]
Cocaine modulates MOR protein and mRNA levels, and protein half-life The effect of cocaine on MOR protein levels was evaluated in extracts of control and treated PC12 cells using western blot analysis
Summary
Cocaine exposure has been reported to alter central μ-opioid receptor (MOR) expression in vivo. Endogenous opioid systems are involved in several aspects of cocaine addiction [1,2,3,4,5], and several studies have indicated that cocaine increases μ-opioid receptor (MOR) mRNA and peptide expression [6,7,8,9,10,11] in regions of the brain known to regulate incentive motivation and stress reactivity [12,13,14]. Cocaine-induced increases in MOR mRNA expression have been consistently observed in the ventral striatum [15,16], a region of the brain critical to drug motivated behaviors [17,18]. Because the promoter region of the MOR gene contains consensus sequences for AP-1 transcription factors [33], it is possible that cocaine modulates MOR expression via alterations in NO and AP-1 activity.
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