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. 2010 Dec 23;2(12):92.
doi: 10.1186/gm213.

New insights into the roles of microRNAs in drug addiction and neuroplasticity

Jean-Luc Dreyer  1
Affiliations

New insights into the roles of microRNAs in drug addiction and neuroplasticity

Jean-Luc Dreyer. Genome Med. .

Abstract

Drug addiction is a major public health issue. It is typically a multigenetic brain disorder, implying combined changes of expression of several hundred genes. Psychostimulants (such as cocaine, heroin and amphetamines) induce strong and persistent neuroadaptive changes through a surfeit of gene regulatory mechanisms leading to addiction. Activity-dependent synaptic plasticity of the mesolimbic dopaminergic system, known as the 'reward pathway', plays a crucial role in the development of drug dependence. miRNAs are small non-coding RNAs, particularly abundant in the nervous system, that play key roles as regulatory molecules in processes such as neurogenesis, synapse development and plasticity in the brain. They also act as key spatiotemporal regulators during dendritic morphogenesis, controlling the expression of hundreds of genes involved in neuroplasticity and in the function of synapses. Recent studies have identified changes of several specific miRNA expression profiles and polymorphisms affecting the interactions between miRNAs and their targets in various brain disorders, including addiction: miR-16 causes adaptive changes in production of the serotonin transporter; miR-133b is specifically expressed in midbrain dopaminergic neurons, and regulates the production of tyrosine hydroxylase and the dopamine transporter; miR-212 affects production of striatal brain-derived neurotrophic factor and synaptic plasticity upon cocaine. Clearly, specific miRNAs have emerged as key regulators leading to addiction, and could serve as valuable targets for more efficient therapies. In this review, the aim is to provide an overview of the emerging role of miRNAs in addiction.

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Figures

Figure 1
Figure 1
Simplified overview of the pathways involved in miRNA regulation of gene expression in addiction. Neurotransmitters activate intracellular signaling pathways through binding to their different receptors, leading to activation of transcription factors. Transcriptional activation induces transcription of a large program of plasticity-related genes - leading to synaptic adaptation and favoring the formation of the addictive phenotype - together with transcription of primer miRNAs. Primer miRNAs are processed by Drosha/DGCR8, and then exported by exportin 5 as precursor miRNAs to be converted to mature miRNA by Dicer and other nucleases. Upon strand selection, the selected strand of the mature miRNA binds with Ago2 and the Risc complex to interact with its specific target. Perfect match with the target mRNA induces deadenylation and mRNA cleavage, while imperfect match prevents binding to ribosomes and blocks translation: in both cases expression is silenced. In many cases, miRNAs regulate gene expression (including plasticity-related genes) in a dynamic double negative feedback loop, as exemplified here with miR-181a/miR-124/let-7 d, involved in cocaine (adapted from [10,11]): the brain-enriched miR-124 is suppressed by chronic cocaine in the mesolimbic dopaminergic pathway (presumably by the induction of REST), which induces expression of genes encoding miR-124 targets (BDNF, integrin β1, NAC1, axon guidance molecules such as SEMA6A, and so on), while downregulation of let-7 d by cocaine results in induction of the genes encoding its targets (μ-opioid receptor, dopamine receptor D3R, semaphorins SEMA6A and SEM4C, PLAU, and so on); these genes (upregulated by cocaine) markedly induce miR-181a, causing downregulation of its targets (RGS4, PI4K2B, Per2, and so on), which in turn regulate expression of miR-124a and let-7 d. Abbreviations: Ago2, argonaute 2; ATF2, cAMP-dependent transcription factor 2; BDNF, brain-derived neurotrophic factor; CREB, cAMP-responsive element binding protein; DGCR8, DiGeorge syndrome critical region protein 8; Dicer, double-stranded RNA endoribonuclease III; 4E-BP, translational repressor protein; eEF1A, elongation factor 1A; eIF-4E, eukaryotic translation initiation factor 4E; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3 kinase; PKA, protein kinase A; PLCγ: phospholipase C-γ; Risc, RNA-induced silencing complex; STAT4, signal transducer and activator of transcription protein 4; S6, ribosomal protein S6 kinase.
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