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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

Enriched synaptic long-term potentiation canonical pathway,identified by ingenuity pathway analysis based on differentially expressed genes(P value < 0.05)with the ordinary student’st-test. The pathway was also detected by onto-tools pathway-express. (A) Week 8 TPM group (29 genes: ATF2, CAMK2D, CAMK2G, CREB1, EP300, GNAQ, GRINA, MAP2K1, MAPK1, MAPK3, PLCB2, PPP1CA, PPP1CB, PPP1CC, PPP1R10, PPP1R12A, PPP1R14B, PPP1R7, PPP3CB, PPP3CC, PRKACA, PRKACB, PRKAR1A, PRKCD, PRKCH, PRKCI, PRKCQ, PRKCZ, and RRAS); and (B) Week 12 TPM group (10 genes; ATF4, CREB5, EP300, GNAQ, KRAS, PPP1R10, PRKACB, PRKAR2A, PRKCB, and PRKCQ). Symbols with a single border represent single genes; those with a double border represent complexes of genes or the possibility that alternative genes might act in the pathway. Red symbols represent up-regulated gene clusters and green symbols represent down-regulated clusters.
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Fig1: Enriched synaptic long-term potentiation canonical pathway,identified by ingenuity pathway analysis based on differentially expressed genes(P value < 0.05)with the ordinary student’st-test. The pathway was also detected by onto-tools pathway-express. (A) Week 8 TPM group (29 genes: ATF2, CAMK2D, CAMK2G, CREB1, EP300, GNAQ, GRINA, MAP2K1, MAPK1, MAPK3, PLCB2, PPP1CA, PPP1CB, PPP1CC, PPP1R10, PPP1R12A, PPP1R14B, PPP1R7, PPP3CB, PPP3CC, PRKACA, PRKACB, PRKAR1A, PRKCD, PRKCH, PRKCI, PRKCQ, PRKCZ, and RRAS); and (B) Week 12 TPM group (10 genes; ATF4, CREB5, EP300, GNAQ, KRAS, PPP1R10, PRKACB, PRKAR2A, PRKCB, and PRKCQ). Symbols with a single border represent single genes; those with a double border represent complexes of genes or the possibility that alternative genes might act in the pathway. Red symbols represent up-regulated gene clusters and green symbols represent down-regulated clusters.

Mentions: The essential pathways related to neuronal function/synaptic plasticity include alpha-adrenergic signaling, ephrin receptor signaling, ErbB signaling, FGF signaling, GnRH signaling, mTOR signaling, neurotrophin/TRK signaling, and synaptic long-term potentiation. The genes in the synaptic long-term potentiation pathway that were changed by TPM at Week 8 and Week 12 are depicted in Figure 1.Figure 1


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)

Enriched synaptic long-term potentiation canonical pathway,identified by ingenuity pathway analysis based on differentially expressed genes(P value < 0.05)with the ordinary student’st-test. The pathway was also detected by onto-tools pathway-express. (A) Week 8 TPM group (29 genes: ATF2, CAMK2D, CAMK2G, CREB1, EP300, GNAQ, GRINA, MAP2K1, MAPK1, MAPK3, PLCB2, PPP1CA, PPP1CB, PPP1CC, PPP1R10, PPP1R12A, PPP1R14B, PPP1R7, PPP3CB, PPP3CC, PRKACA, PRKACB, PRKAR1A, PRKCD, PRKCH, PRKCI, PRKCQ, PRKCZ, and RRAS); and (B) Week 12 TPM group (10 genes; ATF4, CREB5, EP300, GNAQ, KRAS, PPP1R10, PRKACB, PRKAR2A, PRKCB, and PRKCQ). Symbols with a single border represent single genes; those with a double border represent complexes of genes or the possibility that alternative genes might act in the pathway. Red symbols represent up-regulated gene clusters and green symbols represent down-regulated clusters.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Enriched synaptic long-term potentiation canonical pathway,identified by ingenuity pathway analysis based on differentially expressed genes(P value < 0.05)with the ordinary student’st-test. The pathway was also detected by onto-tools pathway-express. (A) Week 8 TPM group (29 genes: ATF2, CAMK2D, CAMK2G, CREB1, EP300, GNAQ, GRINA, MAP2K1, MAPK1, MAPK3, PLCB2, PPP1CA, PPP1CB, PPP1CC, PPP1R10, PPP1R12A, PPP1R14B, PPP1R7, PPP3CB, PPP3CC, PRKACA, PRKACB, PRKAR1A, PRKCD, PRKCH, PRKCI, PRKCQ, PRKCZ, and RRAS); and (B) Week 12 TPM group (10 genes; ATF4, CREB5, EP300, GNAQ, KRAS, PPP1R10, PRKACB, PRKAR2A, PRKCB, and PRKCQ). Symbols with a single border represent single genes; those with a double border represent complexes of genes or the possibility that alternative genes might act in the pathway. Red symbols represent up-regulated gene clusters and green symbols represent down-regulated clusters.
Mentions: The essential pathways related to neuronal function/synaptic plasticity include alpha-adrenergic signaling, ephrin receptor signaling, ErbB signaling, FGF signaling, GnRH signaling, mTOR signaling, neurotrophin/TRK signaling, and synaptic long-term potentiation. The genes in the synaptic long-term potentiation pathway that were changed by TPM at Week 8 and Week 12 are depicted in Figure 1.Figure 1

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