Sex-specific nicotine sensitization and imprinting of self-administration in rats inform GWAS findings on human addiction phenotypes.
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
02
12
2020
accepted:
22
04
2021
revised:
26
03
2021
pubmed:
20
5
2021
medline:
28
8
2021
entrez:
19
5
2021
Statut:
ppublish
Résumé
Repeated nicotine exposure leads to sensitization (SST) and enhances self-administration (SA) in rodents. However, the molecular basis of nicotine SST and SA and their biological relevance to the mounting genome-wide association study (GWAS) loci of human addictive behaviors are poorly understood. Considering a gateway drug role of nicotine, we modeled nicotine SST and SA in F1 progeny of inbred rats (F344/BN) and conducted integrative genomics analyses. We unexpectedly observed male-specific nicotine SST and a parental effect of SA only present in paternal F344 crosses. Transcriptional profiling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) core and shell further revealed sex- and brain region-specific transcriptomic signatures of SST and SA. We found that genes associated with SST and SA were enriched for those related to synaptic processes, myelin sheath, and tobacco use disorder or chemdependency. Interestingly, SST-associated genes were often downregulated in male VTA but upregulated in female VTA, and strongly enriched for smoking GWAS risk variants, possibly explaining the male-specific SST. For SA, we found widespread region-specific allelic imbalance of expression (AIE), of which genes showing AIE bias toward paternal F344 alleles in NAc core were strongly enriched for SA-associated genes and for GWAS risk variants of smoking initiation, likely contributing to the parental effect of SA. Our study suggests a mechanistic link between transcriptional changes underlying the NIC SST and SA and human nicotine addiction, providing a resource for understanding the neurobiology basis of the GWAS findings on human smoking and other addictive phenotypes.
Identifiants
pubmed: 34007041
doi: 10.1038/s41386-021-01027-0
pii: 10.1038/s41386-021-01027-0
pmc: PMC8358005
doi:
Substances chimiques
Nicotine
6M3C89ZY6R
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1746-1756Subventions
Organisme : NIA NIH HHS
ID : R01 AG063175
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH106575
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH116281
Pays : United States
Organisme : NIDA NIH HHS
ID : R21 DA041600
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Caille S, Clemens K, Stinus L, Cador M. Modeling nicotine addiction in rats. Methods Mol Biol. 2012;829:243–56.
pubmed: 22231818
doi: 10.1007/978-1-61779-458-2_15
Vezina P, McGehee DS, Green WN. Exposure to nicotine and sensitization of nicotine-induced behaviors. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31:1625–38.
doi: 10.1016/j.pnpbp.2007.08.038
Levine A, Huang Y, Drisaldi B, Griffin EA Jr, Pollak DD, Xu S, et al. Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine. Sci Transl Med. 2011;3:107ra09.
doi: 10.1126/scitranslmed.3003062
Wain LV, Shrine N, Miller S, Jackson VE, Ntalla I, Soler Artigas M, et al. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir Med. 2015;3:769–81.
pubmed: 26423011
pmcid: 4593935
doi: 10.1016/S2213-2600(15)00283-0
Tobacco, Genetics C. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet. 2010;42:441–7.
doi: 10.1038/ng.571
Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, et al. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet. 2010;42:448–53.
pubmed: 20418888
pmcid: 3080600
doi: 10.1038/ng.573
Bloom AJ, Baker TB, Chen LS, Breslau N, Hatsukami D, Bierut LJ, et al. Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms. Hum Mol Genet. 2014;23:555–61.
pubmed: 24045616
doi: 10.1093/hmg/ddt432
Erzurumluoglu AM, Liu M, Jackson VE, Barnes DR, Datta G, Melbourne CA, et al. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Mol Psychiatry. 2020;25:2392–409.
pubmed: 30617275
doi: 10.1038/s41380-018-0313-0
Liu M, Jiang Y, Wedow R, Li Y, Brazel DM, Chen F, et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet. 2019;51:237–44.
pubmed: 30643251
pmcid: 6358542
doi: 10.1038/s41588-018-0307-5
Marinelli M, White FJ. Enhanced vulnerability to cocaine self-administration is associated with elevated impulse activity of midbrain dopamine neurons. J Neurosci. 2000;20:8876–85.
pubmed: 11102497
pmcid: 6773051
doi: 10.1523/JNEUROSCI.20-23-08876.2000
Schoffelmeer AN, De Vries TJ, Wardeh G, van de Ven HW, Vanderschuren LJ. Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation. J Neurosci. 2002;22:3269–76.
pubmed: 11943828
pmcid: 6757535
doi: 10.1523/JNEUROSCI.22-08-03269.2002
Baker LK, Mao D, Chi H, Govind AP, Vallejo YF, Iacoviello M, et al. Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitises locomotor responding to the drug. Eur J Neurosci. 2013;37:1004–11.
pubmed: 23331514
pmcid: 3604051
doi: 10.1111/ejn.12114
Neugebauer NM, Cortright JJ, Sampedro GR, Vezina P. Exposure to nicotine enhances its subsequent self-administration: contribution of nicotine-associated contextual stimuli. Behav Brain Res. 2014;260:155–61.
pubmed: 24295728
doi: 10.1016/j.bbr.2013.11.035
Kanlikilicer P, Zhang D, Dragomir A, Akay YM, Akay M. Gene expression profiling of midbrain dopamine neurons upon gestational nicotine exposure. Med Biol Eng Comput. 2017;55:467–82.
pubmed: 27255453
doi: 10.1007/s11517-016-1531-8
Yang J, Long Y, Xu DM, Zhu BL, Deng XJ, Yan Z, et al. Age- and nicotine-associated gene expression changes in the hippocampus of APP/PS1 mice. J Mol Neurosci. 2019;69:608–22.
pubmed: 31399937
doi: 10.1007/s12031-019-01389-7
Liang D, Wang KJ, Tang ZQ, Liu RH, Zeng F, Cheng MY, et al. Effects of nicotine on the metabolism and gene expression profile of SpragueDawley rat primary osteoblasts. Mol Med Rep. 2018;17:8269–81.
pubmed: 29658611
pmcid: 5984003
Cortright JJ, Sampedro GR, Neugebauer NM, Vezina P. Previous exposure to nicotine enhances the incentive motivational effects of amphetamine via nicotine-associated contextual stimuli. Neuropsychopharmacology. 2012;37:2277–84.
pubmed: 22617358
pmcid: 3422492
doi: 10.1038/npp.2012.80
Singer BF, Tanabe LM, Gorny G, Jake-Matthews C, Li Y, Kolb B, et al. Amphetamine-induced changes in dendritic morphology in rat forebrain correspond to associative drug conditioning rather than nonassociative drug sensitization. Biol Psychiatry. 2009;65:835–40.
pubmed: 19200535
pmcid: 2743186
doi: 10.1016/j.biopsych.2008.12.020
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. San Diego, CA: Academic Press; 1997.
Forrest MP, Zhang H, Moy W, McGowan H, Leites C, Dionisio LE, et al. Open chromatin profiling in hiPSC-derived neurons prioritizes functional noncoding psychiatric risk variants and highlights neurodevelopmental loci. Cell Stem Cell. 2017;21:305–18.
pubmed: 28803920
pmcid: 5591074
doi: 10.1016/j.stem.2017.07.008
Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018;34:i884–90.
pubmed: 30423086
pmcid: 6129281
doi: 10.1093/bioinformatics/bty560
Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, et al. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature. 2004;428:493–521.
pubmed: 15057822
doi: 10.1038/nature02426
Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C. Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. 2017;14:417–9.
pubmed: 28263959
pmcid: 5600148
doi: 10.1038/nmeth.4197
Soneson C, Love MI, Robinson MD. Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Research. 2015;4:1521.
pubmed: 26925227
doi: 10.12688/f1000research.7563.1
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Love MI, Anders S, Kim V, Huber W. RNA-Seq workflow: gene-level exploratory analysis and differential expression. F1000Res. 2015;4:1070.
pubmed: 26674615
pmcid: 4670015
doi: 10.12688/f1000research.7035.1
Dobin A, Gingeras TR. Optimizing RNA-seq mapping with STAR. Methods Mol. Biol. 2016;1415:245–62.
pubmed: 27115637
doi: 10.1007/978-1-4939-3572-7_13
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.
pubmed: 20644199
pmcid: 2928508
doi: 10.1101/gr.107524.110
Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–2.
pubmed: 20110278
pmcid: 2832824
doi: 10.1093/bioinformatics/btq033
Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.
pubmed: 19131956
doi: 10.1038/nprot.2008.211
Becker KG, Barnes KC, Bright TJ, Wang SA. The genetic association database. Nat Genet. 2004;36:431–2.
pubmed: 15118671
doi: 10.1038/ng0504-431
Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28:27–30.
pubmed: 10592173
pmcid: 102409
doi: 10.1093/nar/28.1.27
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–13.
pubmed: 30476243
doi: 10.1093/nar/gky1131
de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015;11:e1004219.
pubmed: 25885710
pmcid: 4401657
doi: 10.1371/journal.pcbi.1004219
Butler Iii Robert R, Kozlova A, Zhang H, Zhang S, Streit M, Sanders Alan R, et al. The genetic relevance of human induced pluripotent stem cell-derived microglia to Alzheimer’s disease and major neuropsychiatric disorders. Mol. Neuropsychiatry. 2020;5(Suppl 1):85–96.
pubmed: 32399472
Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, et al. Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum Mol Genet. 2018;27:3641–9.
pubmed: 30124842
pmcid: 6488973
doi: 10.1093/hmg/ddy271
Gregg C, Zhang J, Weissbourd B, Luo S, Schroth GP, Haig D, et al. High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science. 2010;329:643–8.
pubmed: 20616232
pmcid: 3005244
doi: 10.1126/science.1190830
Sittig LJ, Redei EE. Novel polymorphisms within the Dlk1-Dio3 imprinted locus in rat: a putative genetic basis for strain-specific allelic gene expression. Front Genet. 2012;3:296.
pubmed: 23248649
pmcid: 3522107
doi: 10.3389/fgene.2012.00296
Lawson HA, Cheverud JM, Wolf JB. Genomic imprinting and parent-of-origin effects on complex traits. Nat Rev Genet. 2013;14:609–17.
pubmed: 23917626
pmcid: 3926806
doi: 10.1038/nrg3543
Illenberger JM, Mactutus CF, Booze RM, Harrod SB. Testing environment shape differentially modulates baseline and nicotine-induced changes in behavior: sex differences, hypoactivity, and behavioral sensitization. Pharmacol Biochem Behav. 2018;165:14–24.
pubmed: 29273458
doi: 10.1016/j.pbb.2017.12.003
Quigley JA, Logsdon MK, Turner CA, Gonzalez IL, Leonardo NB, Becker JB. Sex differences in vulnerability to addiction. Neuropharmacology. 2021;187:108491.
pubmed: 33567305
doi: 10.1016/j.neuropharm.2021.108491
pmcid: 7979496
Becker JB, Prendergast BJ, Liang JW. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol Sex Differ. 2016;7:34.
pubmed: 27468347
pmcid: 4962440
doi: 10.1186/s13293-016-0087-5
Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37:1–13.
pubmed: 19033363
doi: 10.1093/nar/gkn923
von Mering C, Jensen LJ, Snel B, Hooper SD, Krupp M, Foglierini M, et al. STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res. 2005;33:D433–7.
doi: 10.1093/nar/gki005
Khariv V, Ni L, Ratnayake A, Sampath S, Lutz BM, Tao XX, et al. Impaired sensitivity to pain stimuli in plasma membrane calcium ATPase 2 (PMCA2) heterozygous mice: a possible modality- and sex-specific role for PMCA2 in nociception. FASEB J. 2017;31:224–37.
pubmed: 27702770
doi: 10.1096/fj.201600541r
Khariv V, Acioglu C, Ni L, Ratnayake A, Li L, Tao YX, et al. A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor alpha signaling in mechanical pain. Sci Rep. 2018;8:17260.
pubmed: 30467368
pmcid: 6250714
doi: 10.1038/s41598-018-35263-0
Miyazaki K, Mapendano CK, Fuchigami T, Kondo S, Ohta T, Kinoshita A, et al. Developmentally dynamic changes of DNA methylation in the mouse Snurf/Snrpn gene. Gene. 2009;432:97–101.
pubmed: 19095049
doi: 10.1016/j.gene.2008.11.019
Reed ML, Leff SE. Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome. Nat Genet. 1994;6:163–7.
pubmed: 7512861
doi: 10.1038/ng0294-163
Hsiao JS, Germain ND, Wilderman A, Stoddard C, Wojenski LA, Villafano GJ, et al. A bipartite boundary element restricts UBE3A imprinting to mature neurons. Proc Natl Acad Sci USA. 2019;116:2181–6.
pubmed: 30674673
pmcid: 6369781
doi: 10.1073/pnas.1815279116
Sanchez Delgado M, Camprubi C, Tumer Z, Martinez F, Mila M, Monk D. Screening individuals with intellectual disability, autism and Tourette’s syndrome for KCNK9 mutations and aberrant DNA methylation within the 8q24 imprinted cluster. Am J Med Genet B Neuropsychiatr Genet. 2014;165B:472–8.
pubmed: 24980697
doi: 10.1002/ajmg.b.32250
Harrod SB, Mactutus CF, Bennett K, Hasselrot U, Wu G, Welch M, et al. Sex differences and repeated intravenous nicotine: behavioral sensitization and dopamine receptors. Pharmacol Biochem Behav. 2004;78:581–92.
pubmed: 15251267
doi: 10.1016/j.pbb.2004.04.026
Booze RM, Welch MA, Wood ML, Billings KA, Apple SR, Mactutus CF. Behavioral sensitization following repeated intravenous nicotine administration: gender differences and gonadal hormones. Pharmacol Biochem Behav. 1999;64:827–39.
pubmed: 10593207
doi: 10.1016/S0091-3057(99)00169-0
Pehrson AL, Philibin SD, Gross D, Robinson SE, Vann RE, Rosecrans JA, et al. The effects of acute and repeated nicotine doses on spontaneous activity in male and female Sprague Dawley rats: analysis of brain area epibatidine binding and cotinine levels. Pharmacol Biochem Behav. 2008;89:424–31.
pubmed: 18313740
doi: 10.1016/j.pbb.2008.01.018
Cao J, Wang J, Dwyer JB, Gautier NM, Wang S, Leslie FM, et al. Gestational nicotine exposure modifies myelin gene expression in the brains of adolescent rats with sex differences. Transl Psychiatry. 2013;3:e247.
pubmed: 23591971
pmcid: 3641408
doi: 10.1038/tp.2013.21
Cao J, Dwyer JB, Gautier NM, Leslie FM, Li MD. Central myelin gene expression during postnatal development in rats exposed to nicotine gestationally. Neurosci Lett. 2013;553:115–20.
pubmed: 23962570
doi: 10.1016/j.neulet.2013.08.012
Saher G, Stumpf SK. Cholesterol in myelin biogenesis and hypomyelinating disorders. Biochim Biophys Acta. 2015;1851:1083–94.
pubmed: 25724171
doi: 10.1016/j.bbalip.2015.02.010
Bartzokis G. Brain myelination in prevalent neuropsychiatric developmental disorders: primary and comorbid addiction. Adolesc Psychiatry. 2005;29:55–96.
pubmed: 18668184
pmcid: 2490819
Higgins ST, Kurti AN, Redner R, White TJ, Gaalema DE, Roberts ME, et al. A literature review on prevalence of gender differences and intersections with other vulnerabilities to tobacco use in the United States, 2004–2014. Prev Med. 2015;80:89–100.
pubmed: 26123717
pmcid: 4592404
doi: 10.1016/j.ypmed.2015.06.009
Montalban-Loro R, Lozano-Urena A, Ito M, Krueger C, Reik W, Ferguson-Smith AC, et al. TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn. Nat Commun. 2019;10:1726.
pubmed: 30979904
pmcid: 6461695
doi: 10.1038/s41467-019-09665-1
Court F, Camprubi C, Garcia CV, Guillaumet-Adkins A, Sparago A, Seruggia D, et al. The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus. Epigenetics Chromatin. 2014;7:5.
pubmed: 24667089
pmcid: 3986935
doi: 10.1186/1756-8935-7-5
Zhang S, Zhang H, Zhou Y, Qiao M, Zhao S, Kozlova A, et al. Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants. Science. 2020;369:561–5.
pubmed: 32732423
pmcid: 7773145
doi: 10.1126/science.aay3983
Forrest MP, Zhang H, Moy W, McGowan H, Leites C, Dionisio LE, et al. Open chromatin profiling in hiPSC-derived neurons prioritizes functional noncoding psychiatric risk variants and highlights neurodevelopmental loci. Cell Stem Cell. 2017;21:305–18.e8.
pubmed: 28803920
pmcid: 5591074
doi: 10.1016/j.stem.2017.07.008
Walker DM, Cates HM, Loh YE, Purushothaman I, Ramakrishnan A, Cahill KM, et al. Cocaine Self-administration alters transcriptome-wide responses in the brain’s reward circuitry. Biol Psychiatry. 2018;84:867–80.
pubmed: 29861096
pmcid: 6202276
doi: 10.1016/j.biopsych.2018.04.009
Zhou H, Sealock JM, Sanchez-Roige S, Clarke TK, Levey DF, Cheng Z, et al. Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits. Nat Neurosci. 2020;23:809–18.
pubmed: 32451486
pmcid: 7485556
doi: 10.1038/s41593-020-0643-5
Kranzler HR, Zhou H, Kember RL, Vickers Smith R, Justice AC, Damrauer S, et al. Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations. Nat Commun. 2019;10:1499.
pubmed: 30940813
pmcid: 6445072
doi: 10.1038/s41467-019-09480-8
Sun Y, Chang S, Liu Z, Zhang L, Wang F, Yue W, et al. Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence. Mol Psychiatry. 2019;26:1152–61.
pubmed: 31462767
doi: 10.1038/s41380-019-0497-y
Chen H, Hiler KA, Tolley EA, Matta SG, Sharp BM. Genetic factors control nicotine self-administration in isogenic adolescent rat strains. PLoS ONE. 2012;7:e44234.
pubmed: 22937166
pmcid: 3429443
doi: 10.1371/journal.pone.0044234
Flores RJ, Uribe KP, Swalve N, O’Dell LE. Sex differences in nicotine intravenous self-administration: A meta-analytic review. Physiol Behav. 2019;203:42–50.
pubmed: 29158125
doi: 10.1016/j.physbeh.2017.11.017
Keshavarz M, Tautz D. The imprinted lncRNA Peg13 regulates sexual preference and the sex-specific brain transcriptome in mice. Proc Natl Acad Sci. 2021;118:e2022172118.
pubmed: 33658376
pmcid: 7958240
doi: 10.1073/pnas.2022172118