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.