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

BACKGROUND AND PURPOSE: Addiction vulnerability involves complex gene X environment interactions leading to a pathological response to drugs. Identification of the genes mediating 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 subject to timed mating and assigned to PNS or control groups. PNS dams were subject to restraint stress (1 hour restraint, 3 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 QTL interacting with PNS regulating initial locomotor response to cocaine (chromosome X, 37.91 to 50.95 Mb) was identified and 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 also identified. Publicly available mRNA expression data were utilized to identify cis-eQTL and transcript covariation with the behavioral phenotype to prioritize candidate genes; including Aifm1.

CONCLUSIONS AND IMPLICATIONS: These QTL encompass genes which may mediate genetic susceptibility to PNS and interact with sex to determine adult responsiveness to cocaine and addiction vulnerability.

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