Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel
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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.
KeywordsCyfip2 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.
- American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (Revised 4th ed.). American Psychiatric Association, Washington, DCGoogle Scholar
- 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
- 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
- Global Commission on Drug Policy (2011) War on drugs: Report of the Global Commission on Drug Policy. Available at http://www.globalcommissionondrugs.org/wp-content/themes/gcdp_v1/pdf/Global_Commission_Report_English.pdf
- 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
- SAMHSA (2013) Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. Available at http://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/NationalFindings/NSDUHresults2012.pdf
- 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
- UNODC (2013) World Drug Report. Available at http://www.unodc.org/unodc/secured/wdr/wdr2013/World_Drug_Report_2013.pdf