MicroRNA expression signature of methamphetamine use and addiction in the rat nucleus accumbens
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Methamphetamine (METH) is a highly addictive psycho-stimulant that induces behavioral changes due to high level of METH-induced dopamine in the brain. Nucleus accumbens (NAc) plays an important role in these changes, especially in drug addiction. However, little is known about the underlying molecular mechanisms of METH-induced addiction. The objective of this study was to establish a behavioral model of METH use and addiction using escalating doses of METH over 15 days and to determine the global miRNA expression profiling in NAc of METH-addicted rats. In the behavioral study, the experimental rats were divided into 3 groups of 9 each: a control group, a single dose METH (5 mg/kg) treatment group and a continuous 15 alternate days METH (0.25, 0.5, 1, 2, 3, 4, 5 mg/kg) treatment group. Following that, six rats in each group were randomly selected for global miRNA profiling. Addiction behavior in rats was established using Conditioned Place Preference task. The analysis of the miRNA profiling in the NAc was performed using Affymetric microarray GeneChip® System. The findings indicated that a continuous 15 alternate days METH treatment rats showed a preference for the drug-paired compartment of the CPP. However, a one-time acute treatment with 5 mg/kg METH did not show any significant difference in preference when compared with controls. Differential profiling of miRNAs indicated that 166 miRNAs were up-regulated and 4 down-regulated in the chronic METH-treatment group when compared to controls. In comparing the chronic treatment group with the acute treatment group, 52 miRNAs were shown to be up-regulated and 7 were down-regulated. MiRNAs including miR-496-3p, miR-194-5p, miR-200b-3p and miR-181a-5p, were found to be significantly associated with METH addiction. Canonical pathway analysis revealed that a high number of METH addiction-related miRNAs play important roles in the MAPK, CREB, G-Protein Couple Receptor and GnRH Signaling pathways. Our results suggest that dynamic changes occur in the expression of miRNAs following METH exposure and addiction.
KeywordsMethamphetamine addiction microRNA profiling nucleus accumbens
standard error of the mean
real-time polymerase chain reaction
RNA Integrity Number
mitogen-activated protein kinases
cAMP response element-binding protein
brain-derived neurotrophic factor
protein kinase A
protein kinase C
Compliance with ethical standards
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
This work was supported by Research University Grant RG443/12HTM from the University of Malaya and High Impact Research (HIR) Ministry of Higher Education (MOHE) Grant H20001-E000025. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Statement of interest
All the authors declare that they have no conflicts of interest to report that could inappropriately influence, or be perceived to influence, this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Armstrong BD, Noguchi KK (2004) The neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine on serotonin, dopamine, and GABA-ergic terminals: an in-vitro autoradiographic study in rats. Neurotoxicology 25:905–914. doi: 10.1016/j.neuro.2004.06.003 CrossRefPubMedGoogle Scholar
- Baron B, Fernandez MA, Carignon S, Toledo F, Buttin G, Debatisse M (1996) GNAI3, GNAT2, AMPD2, GSTM are clustered in 120 kb of Chinese hamster chromosome 1q Mamm. Genome 7:429–432Google Scholar
- Bosch PJ, Benton MC, Macartney-Coxson D, Kivell BM (2015) mRNA and microRNA analysis reveals modulation of biochemical pathways related to addiction in the ventral tegmental area of methamphetamine self-administering rats. BMC Neurosci 16:43. doi: 10.1186/s12868-015-0186-y CrossRefPubMedPubMedCentralGoogle Scholar
- Chandrasekar V, Dreyer JL (2011) Regulation of MiR-124, Let-7d, and MiR-181a in the accumbens affects the expression, extinction, and reinstatement of cocaine-induced conditioned place preference. Neuropsychopharmacology 36:1149–1164. doi: 10.1038/npp.2010.250 CrossRefPubMedPubMedCentralGoogle Scholar
- Coolen M, Bally-Cuif L (2015) MicroRNAs in brain development. In: Sen CK (ed) MicroRNA in regenerative medicine. Elsevier B.V., p 447–488. doi: 10.1016/B978-0-12-405544-5.00018-6
- Karch SB, Drummer O (2001) Karch’s pathology of drug abuse, 3rd edn. CRC Press, New YorkGoogle Scholar
- National Anti-Drug Agency, Ministry of Home Affairs (2015) Drugs information 2014. Available at: http://www.adk.gov.my/html/pdf/buku%20maklumat%20dadah/BUKU%20MAKLUMAT%20DADAH%202014.pdf. Accessed 3 March 2016
- National Institute on Drug Abuse (2015) DrugFacts: nationwide trends. Available: http://www.drugabuse.gov/publications/drugfacts/nationwide-trends. Accessed 3 March 2016
- Prus AJ, James JR, Rosecrans JA (2009) Methods of behavior analysis in neuroscience. 2nd edition. In: Buccafusco JJ (ed) Chapter 4. Conditioned place preference. CRC Press, Boca RatonGoogle Scholar
- Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE (2011) Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology 36:782–792. doi: 10.1038/npp.2010.212 CrossRefPubMedGoogle Scholar
- Rufer M, Wirth SB, Hofer A, Dermietzel R, Pastor A, Kettenmann H, Unsicker K (1996) Regulation of connexin-43, GFAP, and FGF-2 is not accompanied by changes in astroglial coupling in MPTP-lesioned, FGF-2-treated parkinsonian mice. J Neurosci Res 46:606–617. doi: 10.1002/(SICI)1097-4547(19961201)46:5<606::AID-JNR9>3.0.CO;2-N CrossRefPubMedGoogle Scholar
- Schwendt M, Rocha A, See RE, Pacchioni AM, McGinty JF, Kalivas PW (2009) Extended methamphetamine self-administration in rats results in a selective reduction of dopamine transporter levels in the prefrontal cortex and dorsal striatum not accompanied by marked monoaminergic depletion. J Pharmacol Exp Ther 331:555–562. doi: 10.1124/jpet.109.155770 CrossRefPubMedPubMedCentralGoogle Scholar
- Wang WX et al (2008b) The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 28:1213–1223. doi: 10.1523/JNEUROSCI.5065-07.2008 CrossRefPubMedPubMedCentralGoogle Scholar
- Yao L, McFarland K, Fan P, Jiang Z, Inoue Y, Diamond I (2005) Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proc Natl Acad Sci U S A 102:8746–8751. doi: 10.1073/pnas.0503419102 CrossRefPubMedPubMedCentralGoogle Scholar