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

Drug addiction is a major public health issue. Drugs of abuse modulate gene expression, and produce their rewarding effects of euphoria or pleasure through an interaction with the mesolimbic dopaminergic system, leading to persistent alterations (neuroplastic, structural and functional) in the reward-related and memory-related brain centers. An overview of the pathways involved in miRNA regulation of gene expression in addiction is shown in Figure 1. Long-term intake of addictive substances such as cocaine, heroin and nicotine, for example, results in neurological adaptations that decrease the sensitivity of an individual to these drugs. Drugs induce persistent perturbation of activity-dependent synaptic plasticity, progressing towards high-risk, drug-seeking behavior and relapse [1], but the molecular mechanisms leading to addiction are poorly understood. Emerging evidence suggests that drug-induced neuroplasticity depends on epigenetic changes in gene expression and post-transcriptional regulation [2,3], because addiction is typically a multigenetic brain disorder, implying combined changes of expression of several hundreds of genes. Tight regulation of such a large array of genes in a very complex behavioral paradox is mediated by a variety of transcriptional and post-transcriptional events that control the expression of individual gene products. Recently, a novel class of highly potent post-transcriptional regulators of gene expression has been described that consist of small (19-25 nucleotides) non-coding RNAs. These miRNAs are considered to be 'master regulators' of gene expression, and they control the translation of target mRNAs, thereby regulating critical aspects of neuroplasticity and synapse consolidation. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Targeted mRNAs are selectively and reversibly suppressed translationally or subjected to degradation by miRNAs