MicroRNAs in addiction: adaptation's middlemen? - PubMed (original) (raw)

Review

. 2011 Dec;16(12):1159-68.

doi: 10.1038/mp.2011.58. Epub 2011 May 24.

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Review

MicroRNAs in addiction: adaptation's middlemen?

M D Li et al. Mol Psychiatry. 2011 Dec.

Abstract

A central question in addiction is how drug-induced changes in synaptic signaling are converted into long-term neuroadaptations. Emerging evidence reveals that microRNAs (miRNAs) have a distinct role in this process through rapid response to cellular signals and dynamic regulation of local mRNA transcripts. Because each miRNA can target hundreds of mRNAs, relative changes in the expression of miRNAs can greatly impact cellular responsiveness, synaptic plasticity and transcriptional events. These diverse consequences of miRNA action occur through coordination with genes implicated in addictions, the most compelling of these being the neurotrophin BDNF, the transcription factor cAMP-responsive element-binding protein (CREB) and the DNA-binding methyl CpG binding protein 2 (MeCP2). In this study, we review the recent progress in the understanding of miRNAs in general mechanisms of plasticity and neuroadaptation and then focus on specific examples of miRNA regulation in the context of addiction. We conclude that miRNA-mediated gene regulation is a conserved means of converting environmental signals into neuronal response, which holds significant implications for addiction and other psychiatric illnesses.

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Figures

Figure 1

Figure 1

Relation between miR-212, methyl CpG-binding protein (MeCP2), and brain-derived neurotrophic factor (BDNF) mediates the adaptive response to chronic cocaine exposure. Cocaine increases BDNF concentrations, even after a single dose, and BDNF has a strong role in the motivating and rewarding aspects of the drug. BDNF signaling at the synapse increases transcription of miR-212 via an extracellular-signal-related kinase (ERK1/2) pathway. This miRNA exhibits mutual inhibition with MeCP2, a transcription factor necessary for BDNF expression in response to neural activity. The increased expression of miR-212 observed after chronic cocaine treatment therefore represents a mechanism of tolerance by inhibiting activity-dependent BDNF transcription in the nucleus accumbens.

Figure 2

Figure 2

Decreased miR-124 expression in chronic cocaine conditions allows sustained increases in cAMP response element-binding protein (CREB). miR-124 is important in learning and memory through its inhibition of CREB. Following chronic cocaine exposure, this miRNA is down-regulated, whereas two of its targets, CREB and RE1-silencing transcription factor (REST), are upregulated. Both miR-124 and REST inhibit BDNF expression, so it seems that downregulation of this miRNA marks a shift in the control of BDNF inhibition from miR-124 to REST. This shift allows higher concentrations of CREB, which decreases the rewarding effects of cocaine.

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