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

BMC Medical Genomics

Bankole A Johnson^1,10  Ahmed Elkashef⁹  Elmer Yu⁷  Erin Iturriaga⁹  Roberta Kahn⁹  Christopher Stock⁴  Michael McCann¹  Denis Weis⁵  David J Mawhinney²  William Haning^1,12  Jan Campbell⁸  David Weiss^1,11  Rana Morris³  Jim Saadvandi³  Nassima Ait-Daoud⁶  Chamindi Seneviratne^1,10  Jennie Z Ma⁶  Tianhua Niu⁶  Ju Wang⁶  Ming D Li⁶ 

[1] Matrix Institute on Addictions, West Los Angeles, USA;South Bay Treatment Center, San Diego, USA;Information Management Consultants, Reston, USA;Department of Veterans Affairs, Salt Lake City Health Care System, Salt Lake City, USA;Lutheran Hospital Office of Research, Des Moines, USA;Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA;Veterans Administration Medical Center, Philadelphia, USA;Department of Psychiatry, University of Missouri, Kansas City, USA;Division of Pharmacotherapies and Medical Consequences of Drug Abuse, NIDA, Bethesda, USA;Department of Psychiatry, University of Maryland, Baltimore, USA;Department of Veterans Affairs Cooperative Studies Program Coordination Center, Perry Point, USA;Pacific Addiction Research Center, Honolulu, USA

关键词: Methamphetamine addiction;    Addiction treatment;    Transcriptome;    Pathways;    Genes;    Pharmacogenetics;    Topiramate;   

Others  :  1090103
DOI  :  10.1186/s12920-014-0065-x

 received in 2013-07-31, accepted in 2014-11-19,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Li et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Yang MH, Jung MS, Lee MJ, Yoo KH, Yook YJ, Park EY, Choi SH, Suh YJ, Kim KW, Park JH: Gene expression profiling of the rewarding effect caused by methamphetamine in the mesolimbic dopamine system. Mol Cells 2008, 26(2):121-130.
• [2]Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J: Pharmacotherapy of methamphetamine addiction: an update. Subst Abus 2008, 29(3):31-49.
• [3]SAMHSA: Results from the 2007 National Survey on Drug Use and Health: National Findings.Office of Applied Studies, NSDUH Series H-34, DHHS Publication No. SMA 08–4343. Rockville, MD: 2008.
• [4]Akiyama K, Kanzaki A, Tsuchida K, Ujike H: Methamphetamine-induced behavioral sensitization and its implications for relapse of schizophrenia. Schizophr Res 1994, 12(3):251-257.
• [5]Anglin MD, Burke C, Perrochet B, Stamper E, Dawud-Noursi S: History of the methamphetamine problem. J Psychoactive Drugs 2000, 32(2):137-141.
• [6]Bisagno V, Ferguson D, Luine VN: Short toxic methamphetamine schedule impairs object recognition task in male rats. Brain Res 2002, 940(1–2):95-101.
• [7]Nordahl TE, Salo R, Leamon M: Neuropsychological effects of chronic methamphetamine use on neurotransmitters and cognition: a review. J Neuropsychiatry Clin Neurosci 2003, 15(3):317-325.
• [8]Schroder N, O’Dell SJ, Marshall JF: Neurotoxic methamphetamine regimen severely impairs recognition memory in rats. Synapse 2003, 49(2):89-96.
• [9]Okochi T, Kishi T, Ikeda M, Kitajima T, Kinoshita Y, Kawashima K, Okumura T, Tsunoka T, Inada T, Yamada M, Uchimura N, Iyo M, Sora I, Ozaki N, Ujike H, Iwata N: Genetic association analysis of NRG1 with methamphetamine-induced psychosis in a Japanese population. Prog Neuropsychopharmacol Biol Psychiatry 2009, 33(5):903-905.
• [10]Davidson C, Gow AJ, Lee TH, Ellinwood EH: Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev 2001, 36(1):1-22.
• [11]Ricaurte GA, Guillery RW, Seiden LS, Schuster CR, Moore RY: Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain. Brain Res 1982, 235(1):93-103.
• [12]Rocher C, Gardier AM: Effects of repeated systemic administration of d-Fenfluramine on serotonin and glutamate release in rat ventral hippocampus: comparison with methamphetamine using in vivo microdialysis. Naunyn Schmiedebergs Arch Pharmacol 2001, 363(4):422-428.
• [13]Spina MB, Cohen G: Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci U S A 1989, 86(4):1398-1400.
• [14]Tata DA, Yamamoto BK: Interactions between methamphetamine and environmental stress: role of oxidative stress, glutamate and mitochondrial dysfunction. Addiction 2007, 102(Suppl 1):49-60.
• [15]Yamamoto BK, Zhu W: The effects of methamphetamine on the production of free radicals and oxidative stress. J Pharmacol Exp Ther 1998, 287(1):107-114.
• [16]Zhang X, Lee TH, Xiong X, Chen Q, Davidson C, Wetsel WC, Ellinwood EH: Methamphetamine induces long-term changes in GABAA receptor alpha2 subunit and GAD67 expression. Biochem Biophys Res Commun 2006, 351(1):300-305.
• [17]Johnson BA, Ait-Daoud N, Elkashef AM, Smith EV, Kahn R, Vocci F, Li SH, Bloch DA: A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of methamphetamine dependence. Int J Neuropsychopharmacol 2008, 11(1):1-14.
• [18]Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, Dodgson SP: Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate and related compounds. J Med Chem 1987, 30(5):880-887.
• [19]Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K, Javors MA, Ma JZ: Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 2003, 361(9370):1677-1685.
• [20]Johnson BA, Ait-Daoud N, Akhtar FZ, Javors MA: Use of oral topiramate to promote smoking abstinence among alcohol-dependent smokers: a randomized controlled trial. Arch Intern Med 2005, 165(14):1600-1605.
• [21]Kampman KM, Pettinati H, Lynch KG, Dackis C, Sparkman T, Weigley C, O’Brien CP: A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend 2004, 75(3):233-240.
• [22]Johnson BA, Roache JD, Ait-Daoud N, Wells LT, Wallace CL, Dawes MA, Liu L, Wang XQ: Effects of topiramate on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition in recently abstinent methamphetamine-dependent individuals. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31(1):123-130.
• [23]Johnson BA, Roache JD, Ait-Daoud N, Wells LT, Wallace CL, Dawes MA, Liu L, Wang XQ: Effects of acute topiramate dosing on methamphetamine-induced subjective mood. Int J Neuropsychopharmacol 2007, 10(1):85-98.
• [24]Johnson BA, Wells LT, Roache JD, Wallace CL, Ait-Daoud N, Dawes MA, Liu L, Wang XQ, Javors MA: Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31(2):455-461.
• [25]Zullino DF, Benguettat D, Khazaal Y: Improvement of cognitive performance by topiramate: Blockage of automatic processes may be the underlying mechanism. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31(3):787.
• [26]Elkashef A, Kahn R, Yu E, Iturriaga E, Li SH, Anderson A, Chiang N, Ait-Daoud N, Weiss D, McSherry F, Serpi T, Rawson R, Hrymoc M, Weis D, McCann M, Pham T, Stock C, Dickinson R, Campbell J, Gorodetzky C, Haning W, Carlton B, Mawhinney J, Li MD, Johnson BA: Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial. Addiction 2012, 107(7):1297-1306.
• [27]Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Nitta A, Noda Y, Nabeshima T: Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors. Mol Pharmacol 2004, 65(5):1293-1301.
• [28]Kauer JA, Malenka RC: Synaptic plasticity and addiction. Nat Rev Neurosci 2007, 8(11):844-858.
• [29]Narita M, Miyatake M, Shibasaki M, Tsuda M, Koizumi S, Yajima Y, Inoue K, Suzuki T: Long-lasting change in brain dynamics induced by methamphetamine: enhancement of protein kinase C-dependent astrocytic response and behavioral sensitization. J Neurochem 2005, 93(6):1383-1392.
• [30]Raffa RB, Finno KE, Tallarida CS, Rawls SM: Topiramate-antagonism of L-glutamate-induced paroxysms in planarians. Eur J Pharmacol 2010, 649(1–3):150-153.
• [31]Rawls SM, Thomas T, Adeola M, Patil T, Raymondi N, Poles A, Loo M, Raffa RB: Topiramate antagonizes NMDA- and AMPA-induced seizure-like activity in planarians. Pharmacol Biochem Behav 2009, 93(4):363-367.
• [32]Eun JW, Kwack SJ, Noh JH, Jung KH, Kim JK, Bae HJ, Xie H, Ryu JC, Ahn YM, Park WS, Lee JY, Rhee GS, Nam SW: Identification of post-generation effect of 3,4-methylenedioxymethamphetamine on the mouse brain by large-scale gene expression analysis. Toxicol Lett 2010, 195(1):60-67.
• [33]Simoes PF, Silva AP, Pereira FC, Marques E, Grade S, Milhazes N, Borges F, Ribeiro CF, Macedo TR: Methamphetamine induces alterations on hippocampal NMDA and AMPA receptor subunit levels and impairs spatial working memory. Neuroscience 2007, 150(2):433-441.
• [34]Betancur C, Sakurai T, Buxbaum JD: The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci 2009, 32(7):402-412.
• [35]Schluter OM, Xu W, Malenka RC: Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Neuron 2006, 51(1):99-111.
• [36]Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Walz T, Hayashi Y, Sheng M: Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 2004, 44(3):453-467.
• [37]Mehta S, Wu H, Garner CC, Marshall J: Molecular mechanisms regulating the differential association of kainate receptor subunits with SAP90/PSD-95 and SAP97. J Biol Chem 2001, 276(19):16092-16099.
• [38]Wang L, Piserchio A, Mierke DF: Structural characterization of the intermolecular interactions of synapse-associated protein-97 with the NR2B subunit of N-methyl-D-aspartate receptors. J Biol Chem 2005, 280(29):26992-26996.
• [39]Mauceri D, Gardoni F, Marcello E, Di Luca M: Dual role of CaMKII-dependent SAP97 phosphorylation in mediating trafficking and insertion of NMDA receptor subunit NR2A. J Neurochem 2007, 100(4):1032-1046.
• [40]Suh YH, Terashima A, Petralia RS, Wenthold RJ, Isaac JT, Roche KW, Roche PA: A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking. Nat Neurosci 2010, 13(3):338-343.
• [41]Wienecke J, Westerdahl AC, Hultborn H, Kiehn O, Ryge J: Global gene expression analysis of rodent motor neurons following spinal cord injury associates molecular mechanisms with development of postinjury spasticity. J Neurophysiol 2010, 103(2):761-778.
• [42]Hiraoka S, Kajii Y, Kuroda Y, Umino A, Nishikawa T: The development- and phencyclidine-regulated induction of synapse-associated protein-97 gene in the rat neocortex. Eur Neuropsychopharmacol 2010, 20(3):176-186.
• [43]Takaki M, Ujike H, Kodama M, Takehisa Y, Nakata K, Kuroda S: Two kinds of mitogen-activated protein kinase phosphatases, MKP-1 and MKP-3, are differentially activated by acute and chronic methamphetamine treatment in the rat brain. J Neurochem 2001, 79(3):679-688.
• [44]Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, Steinman L: Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A 2010, 107(6):2580-2585.
• [45]Sequeira A, Turecki G: Genome wide gene expression studies in mood disorders. OMICS 2006, 10(4):444-454.
• [46]Churchill GA: Fundamentals of experimental design for cDNA microarrays. Nat Genet 2002, 32(Suppl 2):490-495.
• [47]van Leeuwen DM, van Agen E, Gottschalk RW, Vlietinck R, Gielen M, van Herwijnen MH, Maas LM, Kleinjans JC, van Delft JH: Cigarette smoke-induced differential gene expression in blood cells from monozygotic twin pairs. Carcinogenesis 2007, 28(3):691-697.
• [48]Lampe JW, Stepaniants SB, Mao M, Radich JP, Dai H, Linsley PS, Friend SH, Potter JD: Signatures of environmental exposures using peripheral leukocyte gene expression: tobacco smoke. Cancer Epidemiol Biomarkers Prev 2004, 13(3):445-453.
• [49]Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, Krainc D: Genome-wide expression profiling of human blood reveals biomarkers for Huntington’s disease. Proc Natl Acad Sci U S A 2005, 102(31):11023-11028.
• [50]Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA, Brown PO: Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci U S A 2003, 100(4):1896-1901.
• [51]Dumeaux V, Johansen J, Borresen-Dale AL, Lund E: Gene expression profiling of whole-blood samples from women exposed to hormone replacement therapy. Mol Cancer Ther 2006, 5(4):868-876.
• [52]Sullivan PF, Fan C, Perou CM: Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 2006, 141B(3):261-268.
• [53]Cai C, Langfelder P, Fuller TF, Oldham MC, Luo R, van den Berg LH, Ophoff RA, Horvath S: Is human blood a good surrogate for brain tissue in transcriptional studies? BMC Genomics 2010, 11:589. BioMed Central Full Text
• [54]Li C: Automating dChip: toward reproducible sharing of microarray data analysis. BMC Bioinformatics 2008, 9:231. BioMed Central Full Text
• [55]Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP: Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003, 31(4):e15.
• [56]Gautier L, Cope L, Bolstad BM, Irizarry RA: Affy–analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 2004, 20(3):307-315.
• [57]Calza S, Raffelsberger W, Ploner A, Sahel J, Leveillard T, Pawitan Y: Filtering genes to improve sensitivity in oligonucleotide microarray data analysis. Nucleic Acids Res 2007, 35(16):e102.
• [58]McClintick JN, Edenberg HJ: Effects of filtering by Present call on analysis of microarray experiments. BMC Bioinformatics 2006, 7:49. BioMed Central Full Text
• [59]Rowe WB, Blalock EM, Chen KC, Kadish I, Wang D, Barrett JE, Thibault O, Porter NM, Rose GM, Landfield PW: Hippocampal expression analyses reveal selective association of immediate-early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats. J Neurosci 2007, 27(12):3098-3110.
• [60]Mutch DM, Berger A, Mansourian R, Rytz A, Roberts MA: The limit fold change model: a practical approach for selecting differentially expressed genes from microarray data. BMC Bioinformatics 2002, 3:17. BioMed Central Full Text
• [61]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Series B 1995, 57(1):289-300.
• [62]Nakatani N, Hattori E, Ohnishi T, Dean B, Iwayama Y, Matsumoto I, Kato T, Osumi N, Higuchi T, Niwa S, Yoshikawa T: Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation. Hum Mol Genet 2006, 15(12):1949-1962.
• [63]Dozmorov MG, Kyker KD, Hauser PJ, Saban R, Buethe DD, Dozmorov I, Centola MB, Culkin DJ, Hurst RE: From microarray to biology: an integrated experimental, statistical and in silico analysis of how the extracellular matrix modulates the phenotype of cancer cells. BMC Bioinformatics 2008, 9(Suppl 9):S4. BioMed Central Full Text
• [64]Draghici S, Khatri P, Tarca AL, Amin K, Done A, Voichita C, Georgescu C, Romero R: A systems biology approach for pathway level analysis. Genome Res 2007, 17(10):1537-1545.
• [65]Khatri P, Sellamuthu S, Malhotra P, Amin K, Done A, Draghici S: Recent additions and improvements to the Onto-Tools. Nucleic Acids Res 2005, 33(Web Server issue):W762-W765.