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Epigenetic inheritance of a cocaine-resistance phenotype

Abstract

We delineated a heritable phenotype resulting from the self-administration of cocaine in rats. We observed delayed acquisition and reduced maintenance of cocaine self-administration in male, but not female, offspring of sires that self-administered cocaine. Brain-derived neurotrophic factor (Bdnf) mRNA and BDNF protein were increased in the medial prefrontal cortex (mPFC), and there was an increased association of acetylated histone H3 with Bdnf promoters in only the male offspring of cocaine-experienced sires. Administration of a BDNF receptor antagonist (the TrkB receptor antagonist ANA-12) reversed the diminished cocaine self-administration in male cocaine-sired rats. In addition, the association of acetylated histone H3 with Bdnf promoters was increased in the sperm of sires that self-administered cocaine. Collectively, these findings indicate that voluntary paternal ingestion of cocaine results in epigenetic reprogramming of the germline, having profound effects on mPFC gene expression and resistance to cocaine reinforcement in male offspring.

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Figure 1: Cocaine self-administration by the F0 sires.
Figure 2: Reduced cocaine intake in male cocaine-sired rats.
Figure 3: Decreased reinforcing effectiveness of cocaine in male cocaine-sired rats.
Figure 4: Increased mPFC BDNF protein and mRNA in male cocaine-sired rats.
Figure 5: Pretreatment with the TrkB antagonist ANA-12 normalized the acquisition of cocaine self-administration in male CocSired rats.
Figure 6: Increased sperm Bdnf promoter acetylation in cocaine-exposed sires.

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Acknowledgements

We thank R. Schassburger, T. Hopkins, B. Kimmey, S. Friedman, A. Lee, S. Darnell and G. Sangrey for technical assistance, and L. Briand for advice on experimental design. This work was supported by grants from the US National Institutes of Health (R01s DA15214, DA22339, DA33641, K02 DA18678, K01 DA30445, F31 DA31535, T32s DA28874 and MH86599).

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F.M.V., S.L.W., H.D.S. and G.S.-V. performed experiments. F.M.V. and R.C.P. analyzed the data, prepared the figures and wrote the first draft of the manuscript. All authors designed experiments and edited the manuscript.

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Correspondence to R Christopher Pierce.

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Vassoler, F., White, S., Schmidt, H. et al. Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16, 42–47 (2013). https://doi.org/10.1038/nn.3280

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