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Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction.

Li MD, Wang J, Niu T, Ma JZ, Seneviratne C, Ait-Daoud N, Saadvandi J, Morris R, Weiss D, Campbell J, Haning W, Mawhinney DJ, Weis D, McCann M, Stock C, Kahn R, Iturriaga E, Yu E, Elkashef A, Johnson BA - BMC Med Genomics (2014)

Bottom Line: The molecular mechanisms underlying its effects are largely unknown.Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups.Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA. Ming_Li@virginia.edu.

ABSTRACT

Background: Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile.

Methods: In this double-blind, placebo-controlled clinical trial, 140 individuals who met the DSM-IV criteria for methamphetamine dependence were randomized to receive either TPM or placebo, of whom 99 consented to participate in our genome-wide expression study. The RNA samples were collected from whole blood for 50 TPM- and 49 placebo-treated participants at three time points: baseline and the ends of weeks 8 and 12. Genome-wide expression profiles and pathways of the two groups were compared for the responders and non-responders at Weeks 8 and 12. To minimize individual variations, expression of all examined genes at Weeks 8 and 12 were normalized to the values at baseline prior to identification of differentially expressed genes and pathways.

Results: At the single-gene level, we identified 1054, 502, 204, and 404 genes at nominal P values < 0.01 in the responders vs. non-responders at Weeks 8 and 12 for the TPM and placebo groups, respectively. Among them, expression of 159, 38, 2, and 21 genes was still significantly different after Bonferroni corrections for multiple testing. Many of these genes, such as GRINA, PRKACA, PRKCI, SNAP23, and TRAK2, which are involved in glutamate receptor and GABA receptor signaling, are direct targets for TPM. In contrast, no TPM drug targets were identified in the 38 significant genes for the Week 8 placebo group. Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups. These pathways are involved in relevant physiological functions such as neuronal function/synaptic plasticity, signal transduction, cardiovascular function, and inflammation/immune function.

Conclusion: Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.

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Related in: MedlinePlus

Integrated model of the biological pathways related to TPM treatment for methamphetamine addiction. The joint effects of TPM and methamphetamine act on multiple molecular pathways that eventually result in modulations of neuroplasticity and neurotoxicity/neurodegeneration, which have a combined effect on cognitive/behavioral function. Pathways enriched exclusively in the TPM responder groups at Weeks 8 and 12 are highlighted in gray.
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Fig2: Integrated model of the biological pathways related to TPM treatment for methamphetamine addiction. The joint effects of TPM and methamphetamine act on multiple molecular pathways that eventually result in modulations of neuroplasticity and neurotoxicity/neurodegeneration, which have a combined effect on cognitive/behavioral function. Pathways enriched exclusively in the TPM responder groups at Weeks 8 and 12 are highlighted in gray.

Mentions: The current study is the first genome-wide expression investigation into the effects of TPM for the treatment of METH dependence. By profiling genome-wide expression patterns in human white blood cells from METH-dependent subjects who received either oral TPM or placebo, we identified various number of genes that are differentially expressed between responders and non-responders in the TPM-treated and placebo control groups. Further clustering of these altered genes according to their function revealed the significantly enriched pathways governing neuroplasticity and neurotoxicity/neurodegeneration (see Figure 2). Given the primary purpose of this clinical trial, in this discussion, we focus primarily on how TPM may regulate molecular pathways of synaptic plasticity underlying METH’s reward and reinforcing effects that influence abstinence.Figure 2


Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction.

Li MD, Wang J, Niu T, Ma JZ, Seneviratne C, Ait-Daoud N, Saadvandi J, Morris R, Weiss D, Campbell J, Haning W, Mawhinney DJ, Weis D, McCann M, Stock C, Kahn R, Iturriaga E, Yu E, Elkashef A, Johnson BA - BMC Med Genomics (2014)

Integrated model of the biological pathways related to TPM treatment for methamphetamine addiction. The joint effects of TPM and methamphetamine act on multiple molecular pathways that eventually result in modulations of neuroplasticity and neurotoxicity/neurodegeneration, which have a combined effect on cognitive/behavioral function. Pathways enriched exclusively in the TPM responder groups at Weeks 8 and 12 are highlighted in gray.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4279796&req=5

Fig2: Integrated model of the biological pathways related to TPM treatment for methamphetamine addiction. The joint effects of TPM and methamphetamine act on multiple molecular pathways that eventually result in modulations of neuroplasticity and neurotoxicity/neurodegeneration, which have a combined effect on cognitive/behavioral function. Pathways enriched exclusively in the TPM responder groups at Weeks 8 and 12 are highlighted in gray.
Mentions: The current study is the first genome-wide expression investigation into the effects of TPM for the treatment of METH dependence. By profiling genome-wide expression patterns in human white blood cells from METH-dependent subjects who received either oral TPM or placebo, we identified various number of genes that are differentially expressed between responders and non-responders in the TPM-treated and placebo control groups. Further clustering of these altered genes according to their function revealed the significantly enriched pathways governing neuroplasticity and neurotoxicity/neurodegeneration (see Figure 2). Given the primary purpose of this clinical trial, in this discussion, we focus primarily on how TPM may regulate molecular pathways of synaptic plasticity underlying METH’s reward and reinforcing effects that influence abstinence.Figure 2

Bottom Line: The molecular mechanisms underlying its effects are largely unknown.Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups.Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA. Ming_Li@virginia.edu.

ABSTRACT

Background: Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile.

Methods: In this double-blind, placebo-controlled clinical trial, 140 individuals who met the DSM-IV criteria for methamphetamine dependence were randomized to receive either TPM or placebo, of whom 99 consented to participate in our genome-wide expression study. The RNA samples were collected from whole blood for 50 TPM- and 49 placebo-treated participants at three time points: baseline and the ends of weeks 8 and 12. Genome-wide expression profiles and pathways of the two groups were compared for the responders and non-responders at Weeks 8 and 12. To minimize individual variations, expression of all examined genes at Weeks 8 and 12 were normalized to the values at baseline prior to identification of differentially expressed genes and pathways.

Results: At the single-gene level, we identified 1054, 502, 204, and 404 genes at nominal P values < 0.01 in the responders vs. non-responders at Weeks 8 and 12 for the TPM and placebo groups, respectively. Among them, expression of 159, 38, 2, and 21 genes was still significantly different after Bonferroni corrections for multiple testing. Many of these genes, such as GRINA, PRKACA, PRKCI, SNAP23, and TRAK2, which are involved in glutamate receptor and GABA receptor signaling, are direct targets for TPM. In contrast, no TPM drug targets were identified in the 38 significant genes for the Week 8 placebo group. Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups. These pathways are involved in relevant physiological functions such as neuronal function/synaptic plasticity, signal transduction, cardiovascular function, and inflammation/immune function.

Conclusion: Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.

Show MeSH
Related in: MedlinePlus