, Volume 233, Issue 4, pp 701–714 | Cite as

Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel

  • Price E. Dickson
  • Mellessa M. Miller
  • Michele A. Calton
  • Jason A. Bubier
  • Melloni N. Cook
  • Daniel Goldowitz
  • Elissa J. Chesler
  • Guy Mittleman
Original Investigation



Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underlying cocaine use in mice.


Mice from 39 BXD strains acquired cocaine IVSA (0.56 mg/kg/infusion). Mice from 29 BXD strains completed a full dose-response curve (0.032–1.8 mg/kg/infusion). We identified independent genetic correlations between cocaine IVSA and measures of environmental exploration and cocaine sensitization. We identified genome-wide significant quantitative trait loci (QTL) on chromosomes 7 and 11 associated with shifts in the dose-response curve and on chromosome 16 associated with sessions to acquire cocaine IVSA. Using publicly available gene expression data from the nucleus accumbens, midbrain, and prefrontal cortex of drug-naïve mice, we identified Aplp1 and Cyfip2 as positional candidates underlying the behavioral QTL on chromosomes 7 and 11, respectively. A genome-wide significant trans-eQTL linking Fam53b (a GWAS candidate for human cocaine dependence) on chromosome 7 to the cocaine IVSA behavioral QTL on chromosome 11 was identified in the midbrain; Fam53b and Cyfip2 were co-expressed genome-wide significantly in the midbrain. This finding indicates that cocaine IVSA studies using mice can identify genes involved in human cocaine use.


These data provide novel candidate genes underlying cocaine IVSA in mice and suggest mechanisms driving human cocaine use.


Cyfip2 Fam53b Aplp1 Addiction QTL eQTL Genetic correlation Cocaine sensitization Open field Light dark box 



This project was made possible by NIDA grant 1R01DA020677. PED and EJC were supported by NIDA grant 1R01DA037927. The authors gratefully acknowledge Drs. Lu Lu and Robert W. Williams for providing new BXD strains, Erin Clardy and Tom Schneider for assistance with behavioral data collection, Lei Yan for technical assistance with GeneNetwork, and Darla Miller.

Supplementary material

213_2015_4147_MOESM1_ESM.pdf (75 kb)
ESM 1 (DOCX 74.8 kb)
213_2015_4147_MOESM2_ESM.pdf (296 kb)
ESM 2 (PDF 296 kb)


  1. Alberts R, Schughart K (2010) QTLminer: identifying genes regulating quantitative traits. BMC Bioinf 11:516CrossRefGoogle Scholar
  2. Albertson DN, Pruetz B, Schmidt CJ, Kuhn DM, Kapatos G, Bannon MJ (2004) Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem 88:1211–1219PubMedCentralCrossRefPubMedGoogle Scholar
  3. Albertson DN, Schmidt CJ, Kapatos G, Bannon MJ (2006) Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology 31:2304–2312PubMedCentralPubMedGoogle Scholar
  4. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (Revised 4th ed.). American Psychiatric Association, Washington, DCGoogle Scholar
  5. Arrant AE, Schramm-Sapyta NL, Kuhn CM (2013) Use of the light/dark test for anxiety in adult and adolescent male rats. Behav Brain Res 256:119–127PubMedCentralCrossRefPubMedGoogle Scholar
  6. Aydin D, Weyer SW, Muller UC (2012) Functions of the APP gene family in the nervous system: insights from mouse models. Exp Brain Res 217:423–434CrossRefPubMedGoogle Scholar
  7. Belknap JK (1998) Effect of within-strain sample size on QTL detection and mapping using recombinant inbred mouse strains. Behav Genet 28:29–38CrossRefPubMedGoogle Scholar
  8. Blanchard MM, Mendelsohn D, Stamp JA (2009) The HR/LR model: further evidence as an animal model of sensation seeking. Neurosci Biobehav Rev 33:1145–1154CrossRefPubMedGoogle Scholar
  9. Bocklisch C, Pascoli V, Wong JC, House DR, Yvon C, de Roo M, Tan KR, Luscher C (2013) Cocaine disinhibits dopamine neurons by potentiation of GABA transmission in the ventral tegmental area. Science 341:1521–1525CrossRefPubMedGoogle Scholar
  10. Cain ME, Saucier DA, Bardo MT (2005) Novelty seeking and drug use: contribution of an animal model. Exp Clin Psychopharmacol 13:367–375CrossRefPubMedGoogle Scholar
  11. Chesler EJ (2014) Out of the bottleneck: the diversity outcross and collaborative cross mouse populations in behavioral genetics research. Mamm Genome 25:3–11PubMedCentralCrossRefPubMedGoogle Scholar
  12. Civelek M, Lusis AJ (2014) Systems genetics approaches to understand complex traits. Nat Rev Genet 15:34–48PubMedCentralCrossRefPubMedGoogle Scholar
  13. Contractor A, Mulle C, Swanson GT (2011) Kainate receptors coming of age: milestones of two decades of research. Trends Neurosci 34:154–163PubMedCentralCrossRefPubMedGoogle Scholar
  14. Cousins SL, Dai W, Stephenson FA (2015) APLP1 and APLP2, members of the APP family of proteins, behave similarly to APP in that they associate with NMDA receptors and enhance NMDA receptor surface expression. J Neurochem 133:879–885CrossRefPubMedGoogle Scholar
  15. Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Laane K, Pena Y, Murphy ER, Shah Y, Probst K, Abakumova I, Aigbirhio FI, Richards HK, Hong Y, Baron JC, Everitt BJ, Robbins TW (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315:1267–1270PubMedCentralCrossRefPubMedGoogle Scholar
  16. Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017CrossRefPubMedGoogle Scholar
  17. Dickson PE, Miller MM, Rogers TD, Blaha CD, Mittleman G (2014) Effects of adolescent nicotine exposure and withdrawal on intravenous cocaine self-administration during adulthood in male C57BL/6J mice. Addict Biol 19:37–48Google Scholar
  18. Ersche KD, Turton AJ, Pradhan S, Bullmore ET, Robbins TW (2010) Drug addiction endophenotypes: impulsive versus sensation-seeking personality traits. Biol Psychiatry 68:770–773PubMedCentralCrossRefPubMedGoogle Scholar
  19. Ersche KD, Turton AJ, Chamberlain SR, Muller U, Bullmore ET, Robbins TW (2012) Cognitive dysfunction and anxious-impulsive personality traits are endophenotypes for drug dependence. Am J Psychiatry 169:926–936PubMedCentralCrossRefPubMedGoogle Scholar
  20. Ersche KD, Jones PS, Williams GB, Smith DG, Bullmore ET, Robbins TW (2013) Distinctive personality traits and neural correlates associated with stimulant drug use versus familial risk of stimulant dependence. Biol Psychiatry 74:137–144PubMedCentralCrossRefPubMedGoogle Scholar
  21. Everitt BJ, Robbins TW (2000) Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology (Berl) 153:17–30CrossRefGoogle Scholar
  22. Gancarz AM, San George MA, Ashrafioun L, Richards JB (2011) Locomotor activity in a novel environment predicts both responding for a visual stimulus and self-administration of a low dose of methamphetamine in rats. Behav Processes 86:295–304PubMedCentralCrossRefPubMedGoogle Scholar
  23. Gelernter J, Sherva R, Koesterer R, Almasy L, Zhao H, Kranzler HR, Farrer L (2014) Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene. Mol Psychiatry 19:717–723PubMedCentralCrossRefPubMedGoogle Scholar
  24. Global Commission on Drug Policy (2011) War on drugs: Report of the Global Commission on Drug Policy. Available at
  25. Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6:521–532CrossRefPubMedGoogle Scholar
  26. Goldstein A, Kalant H (1990) Drug policy: striking the right balance. Science 249:1513–1521CrossRefPubMedGoogle Scholar
  27. Gregus AM, Tropea TF, Wang Y, Hauck SC, Costa AC, Rajadhyaksha AM, Inturrisi CE (2010) Deletion of the GluR5 subunit of kainate receptors affects cocaine sensitivity and preference. Neurosci Lett 468:186–189PubMedCentralCrossRefPubMedGoogle Scholar
  28. Hall FS, Drgonova J, Jain S, Uhl GR (2013) Implications of genome wide association studies for addiction: are our a priori assumptions all wrong? Pharmacol Ther 140:267–279PubMedCentralCrossRefPubMedGoogle Scholar
  29. Ito R, Robbins TW, Everitt BJ (2004) Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci 7:389–397CrossRefPubMedGoogle Scholar
  30. Klebaur JE, Bevins RA, Segar TM, Bardo MT (2001) Individual differences in behavioral responses to novelty and amphetamine self-administration in male and female rats. Behav Pharmacol 12:267–275CrossRefPubMedGoogle Scholar
  31. Korte M, Herrmann U, Zhang X, Draguhn A (2012) The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models. Exp Brain Res 217:435–440CrossRefPubMedGoogle Scholar
  32. Kumar V, Kim K, Joseph C, Kourrich S, Yoo SH, Huang HC, Vitaterna MH, de Villena FP, Churchill G, Bonci A, Takahashi JS (2013) C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342:1508–1512PubMedCentralCrossRefPubMedGoogle Scholar
  33. Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ (2004) Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats. Psychopharmacology (Berl) 175:26–36CrossRefGoogle Scholar
  34. Marinelli M, Cooper DC, Baker LK, White FJ (2003) Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior. Psychopharmacology (Berl) 168:84–98CrossRefGoogle Scholar
  35. Marusich JA, Bardo MT (2009) Differences in impulsivity on a delay-discounting task predict self-administration of a low unit dose of methylphenidate in rats. Behav Pharmacol 20:447–454PubMedCentralCrossRefPubMedGoogle Scholar
  36. Mead AN, Zamanillo D, Becker N, Stephens DN (2007) AMPA-receptor GluR1 subunits are involved in the control over behavior by cocaine-paired cues. Neuropsychopharmacology 32:343–353CrossRefPubMedGoogle Scholar
  37. Mello NK, Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14:375–424CrossRefPubMedGoogle Scholar
  38. Peirce JL, Lu L, Gu J, Silver LM, Williams RW (2004) A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet 5:7PubMedCentralCrossRefPubMedGoogle Scholar
  39. Pettit HO, Ettenberg A, Bloom FE, Koob GF (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology (Berl) 84:167–173CrossRefGoogle Scholar
  40. Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ (2010) High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains. Genes Brain Behav 9:129–159PubMedCentralCrossRefPubMedGoogle Scholar
  41. Piazza PV, Deminiere JM, Maccari S, Mormede P, Le Moal M, Simon H (1990) Individual reactivity to novelty predicts probability of amphetamine self-administration. Behav Pharmacol 1:339–345CrossRefPubMedGoogle Scholar
  42. Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11CrossRefPubMedGoogle Scholar
  43. Roberts DC, Koob GF (1982) Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats. Pharmacol, Biochem Behav 17:901–904CrossRefGoogle Scholar
  44. SAMHSA (2013) Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. Available at
  45. Sanchis-Segura C, Spanagel R (2006) Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addict Biol 11:2–38CrossRefPubMedGoogle Scholar
  46. Schenck A, Bardoni B, Moro A, Bagni C, Mandel JL (2001) A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc Natl Acad Sci U S A 98:8844–8849PubMedCentralCrossRefPubMedGoogle Scholar
  47. Sora I, Li B, Igari M, Hall FS, Ikeda K (2010) Transgenic mice in the study of drug addiction and the effects of psychostimulant drugs. Ann N Y Acad Sci 1187:218–246CrossRefPubMedGoogle Scholar
  48. Thomsen M, Caine SB (2007) Intravenous drug self-administration in mice: practical considerations. Behav Genet 37:101–118CrossRefPubMedGoogle Scholar
  49. Vassoler FM, White SL, Schmidt HD, Sadri-Vakili G, Pierce RC (2013) Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16:42–47PubMedCentralCrossRefPubMedGoogle Scholar
  50. Weissenborn R, Robbins TW, Everitt BJ (1997) Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats. Psychopharmacology (Berl) 134:242–257CrossRefGoogle Scholar
  51. Wise RA (2009) Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction. Trends Neurosci 32:517–524PubMedCentralCrossRefPubMedGoogle Scholar
  52. Wolen AR, Phillips CA, Langston MA, Putman AH, Vorster PJ, Bruce NA, York TP, Williams RW, Miles MF (2012) Genetic dissection of acute ethanol responsive gene networks in prefrontal cortex: functional and mechanistic implications. PLoS One 7, e33575PubMedCentralCrossRefPubMedGoogle Scholar
  53. Ye R, Carneiro AM, Airey D, Sanders-Bush E, Williams RW, Lu L, Wang J, Zhang B, Blakely RD (2014) Evaluation of heritable determinants of blood and brain serotonin homeostasis using recombinant inbred mice. Genes Brain Behav 13:247–260PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Price E. Dickson
    • 1
  • Mellessa M. Miller
    • 3
  • Michele A. Calton
    • 3
  • Jason A. Bubier
    • 1
  • Melloni N. Cook
    • 3
  • Daniel Goldowitz
    • 2
  • Elissa J. Chesler
    • 1
  • Guy Mittleman
    • 3
    • 4
  1. 1.The Jackson LaboratoryBar HarborUSA
  2. 2.Centre for Molecular Medicine and Therapeutics, Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  3. 3.Department of PsychologyUniversity of MemphisMemphisUSA
  4. 4.Department of Psychological ScienceBall State UniversityMuncieUSA

Personalised recommendations