Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Nov;176(21):4159-4172.
doi: 10.1111/bph.14661. Epub 2019 May 11.

Discovery of early life stress interacting and sex-specific quantitative trait loci impacting cocaine responsiveness

Jared R Bagley  1 , Karen K Szumlinski  1   2   3   4 , Tod E Kippin  1   2   3   4
Affiliations

Discovery of early life stress interacting and sex-specific quantitative trait loci impacting cocaine responsiveness

Jared R Bagley et al. Br J Pharmacol. 2019 Nov.

Abstract

Background and purpose: Addiction vulnerability involves complex gene X environment interactions leading to a pathological response to drugs. Identification of the genes involved in these interactions is an important step in understanding the underlying neurobiology and rarely have such analyses examined sex-specific influences. To dissect this interaction, we examined the impact of prenatal stress (PNS) on cocaine responsiveness in male and female mice of the BXD recombinant inbred panel.

Experimental approach: BXD strains were subjected to timed mating and assigned to PNS or control groups. PNS dams were subjected to restraint stress (1-hr restraint, three times daily) starting between embryonic day (E) 11 and 14 and continued until parturition. Adult male and female, control and PNS offspring were tested for locomotor response to initial and repeated cocaine injections (sensitization) as well as cocaine-induced conditioned place preference (CPP).

Key results: Strain, PNS, and sex interacted to modulate initial and sensitized cocaine-induced locomotion, as well as CPP. Moreover, a quantitative trait locus (QTL) interacting with PNS regulating initial locomotor response to cocaine (chromosome X, 37.91 to 50.95 Mb) was identified. Also PNS-independent, female-specific QTLs regulating CPP (chromosome 11, 65.50 to 81.31 Mb) and sensitized cocaine-induced locomotion (chromosome 16, 95.79 to 98.32 Mb) were identified. Publicly available mRNA expression data were utilized to identify cis-eQTL and transcript covariation with the behavioural phenotype to prioritize candidate genes; including Aifm1.

Conclusions and implications: These QTL encompass genes that may moderate genetic susceptibility to PNS and interact with sex to determine adult responsiveness to cocaine and addiction vulnerability.

Linked articles: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Effects of sex, strain, and PNS on cocaine (10‐mg·kg−1 IP X 4) responsiveness in adult BXD mice. Strains are rank ordered on the x axis by the control male means. (a) Acute cocaine‐induced locomotion is impacted by sex X strain and PNS X strain interactions. (b) Sensitization of cocaine‐induced locomotion is impacted by sex X strain and PNS X sex interactions. Within‐sex analysis revealed an effect of PNS in males but not females. (c) Conditioned place preference is impacted by sex X strain and PNS X sex interactions. Within sex analysis revealed an effect of PNS in males but not females. All data are plotted as mean with SEM. # = significant main effect of strain, $ = significant strain by sex interaction, X = significant strain by PNS interaction, @ = significant sex by PNS interaction, * = significant main effect of PNS
Figure 2
Figure 2
PNS interacting QTL impact acute cocaine‐induced locomotion. (a) A significant QTL by PNS interaction on chromosome X. (b) Effects of genotype at the peak marker and PNS on acute locomotion, plotted as mean with SEM (B6 control n = 403, B6 PNS n = 380, D2 control n = 125, D PNS n = 142). (c) Scatter plot of PNS strain effects on acute cocaine‐induced locomotion and striatal expression of Aifm1. (d) Association of striatal Aifm1 expression with striatal D1/D2 receptor expression
Figure 3
Figure 3
Sex‐specific QTLs impacting conditioned place preference (CPP) and sensitization of cocaine‐induced locomotion in females. (a) A significant main effect QTL for female CPP on chromosome 11. (b) Effects of genotype at the peak marker and sex on CPP, plotted as mean with SEM (B6 female n = 114, B6 male n = 118, D2 female n = 411, D2 male n = 409). (c) A significant main effect QTL for female sensitization on chromosome 16. (d) Effects of genotype at the peak marker and sex on sensitization, plotted as mean with SEM (B6 female n = 387, B6 male n = 378, D2 female n = 145, D2 male n = 137)
See this image and copyright information in PMC

References

    1. Agrawal, A. , Verweij, K. J. H. , Gillespie, N. A. , Heath, A. C. , Lessov‐Schlaggar, C. N. , Martin, N. G. , … Lynskey, M. T. (2012). The genetics of addiction—A translational perspective. Translational Psychiatry, 2(7), e140 10.1038/tp.2012.54 - DOI - PMC - PubMed
    1. Alb, J. G. , Cortese, J. D. , Phillips, S. E. , Albin, R. L. , Nagy, T. R. , Hamilton, B. A. , & Bankaitis, V. A. (2003). Mice lacking phosphatidylinositol transfer protein‐α exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia. The Journal of Biological Chemistry, 278(35), 33501–33518. 10.1074/jbc.M303591200 - DOI - PMC - PubMed
    1. Alexander, S. P. , Christopoulos, A. , Davenport, A. P. , Kelly, E. , Marrion, N. V. , Peters, J. A. , … CGTP Collaborators . (2017). The Concise Guide to PHARMACOLOGY 2017/18: G protein‐coupled receptors. British Journal of Pharmacology, 174(Suppl 1), S17–S129. 10.1111/bph.13878 - DOI - PMC - PubMed
    1. Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Marrion, N. V. , Peters, J. A. , Faccenda, E. , … CGTP Collaborators . (2017). The Concise Guide to PHARMACOLOGY 2017/18: Enzymes. British Journal of Pharmacology, 174(S1), S272–S359. 10.1111/bph.13877 - DOI - PMC - PubMed
    1. Bale, T. L. (2011). Sex differences in prenatal epigenetic programing of stress pathways. Stress, 14(4), 348–356. 10.3109/10253890.2011.586447 - DOI - PubMed

Publication types