Psychopharmacology

, 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

Abstract

Rationale

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.

Methods

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.

Conclusions

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

Keywords

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

Notes

Acknowledgments

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)

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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

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