Journal
NATURE NEUROSCIENCE
Volume 16, Issue 1, Pages 42-U67Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3280
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Funding
- US National Institutes of Health [R01s DA15214, DA22339, DA33641, K02 DA18678, K01 DA30445, F31 DA31535, T32s DA28874, MH86599]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007517] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH086599, R56MH086599] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [T32DA028874, K02DA018678, R01DA015214, F31DA031535, R01DA033641, R01DA022339, K01DA030445] Funding Source: NIH RePORTER
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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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