Abstract
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.
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Abbreviations
- miRNA:
-
microRNA
- SEM:
-
standard error of the mean
- qPCR:
-
real-time polymerase chain reaction
- RIN:
-
RNA Integrity Number
- MAPK:
-
mitogen-activated protein kinases
- CREB:
-
cAMP response element-binding protein
- GnRH:
-
Gonadotropin-releasing hormone
- BDNF:
-
brain-derived neurotrophic factor
- PKA:
-
protein kinase A
- PKC:
-
protein kinase C
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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.
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Sim, M.S., Soga, T., Pandy, V. et al. MicroRNA expression signature of methamphetamine use and addiction in the rat nucleus accumbens. Metab Brain Dis 32, 1767–1783 (2017). https://doi.org/10.1007/s11011-017-0061-x
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DOI: https://doi.org/10.1007/s11011-017-0061-x