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      mRNA and microRNA analysis reveals modulation of biochemical pathways related to addiction in the ventral tegmental area of methamphetamine self-administering rats

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          Abstract

          Background

          Methamphetamine is a highly addictive central nervous system stimulant with increasing levels of abuse worldwide. Alterations to mRNA and miRNA expression within the mesolimbic system can affect addiction-like behaviors and thus play a role in the development of drug addiction. While many studies have investigated the effects of high-dose methamphetamine, and identified neurotoxic effects, few have looked at the role that persistent changes in gene regulation play following methamphetamine self-administration. Therefore, the aim of this study was to identify RNA changes in the ventral tegmental area following methamphetamine self-administration. We performed microarray analyses on RNA extracted from the ventral tegmental area of Sprague–Dawley rats following methamphetamine self-administration training (2 h/day) and 14 days of abstinence.

          Results

          We identified 78 miRNA and 150 mRNA transcripts that were differentially expressed (fdr adjusted p < 0.05, absolute log2 fold change >0.5); these included genes not previously associated with addiction (miR-125a-5p, miR-145 and Foxa1), loci encoding receptors related to drug addiction behaviors and genes with previously recognized roles in addiction such as miR-124, miR-181a, DAT and Ret.

          Conclusion

          This study provides insight into the effects of methamphetamine on RNA expression in a key brain region associated with addiction, highlighting the possibility that persistent changes in the expression of genes with both known and previously unknown roles in addiction occur.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12868-015-0186-y) contains supplementary material, which is available to authorized users.

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          Most cited references 56

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          Linear models and empirical Bayes methods for assessing differential expression in microarray experiments

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            A brain-specific microRNA regulates dendritic spine development.

            MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.
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              A MicroRNA feedback circuit in midbrain dopamine neurons.

              MicroRNAs (miRNAs) are evolutionarily conserved, 18- to 25-nucleotide, non-protein coding transcripts that posttranscriptionally regulate gene expression during development. miRNAs also occur in postmitotic cells, such as neurons in the mammalian central nervous system, but their function is less well characterized. We investigated the role of miRNAs in mammalian midbrain dopaminergic neurons (DNs). We identified a miRNA, miR-133b, that is specifically expressed in midbrain DNs and is deficient in midbrain tissue from patients with Parkinson's disease. miR-133b regulates the maturation and function of midbrain DNs within a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3. We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion.
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                Author and article information

                Contributors
                peetyrbosch@gmail.com
                miles.benton84@gmail.com
                donia.macartney@esr.cri.nz
                Bronwyn.kivell@vuw.ac.nz
                Journal
                BMC Neurosci
                BMC Neurosci
                BMC Neuroscience
                BioMed Central (London )
                1471-2202
                19 July 2015
                19 July 2015
                2015
                : 16
                Affiliations
                [ ]Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, PO Box 600, Wellington, 6140 New Zealand
                [ ]Institute of Environmental Science and Research, Wellington, New Zealand
                [ ]Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
                Article
                186
                10.1186/s12868-015-0186-y
                4506769
                © Bosch et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Research Article
                Custom metadata
                © The Author(s) 2015

                Neurosciences

                microrna, self-administration, methamphetamine, genetics, brain

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