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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetylation / drug effects
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Animals
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Animals, Newborn
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Azepines / pharmacology
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Benzamides / pharmacology
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism
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Chromatin Immunoprecipitation
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Cocaine / administration & dosage*
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Cocaine-Related Disorders / genetics
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Conditioning, Operant / drug effects
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Conditioning, Operant / physiology*
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Disease Models, Animal
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Dopamine Uptake Inhibitors / administration & dosage*
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Dose-Response Relationship, Drug
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Epigenomics*
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Feeding Behavior / drug effects
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Female
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Food Preferences / drug effects
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Food Preferences / physiology
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Grooming / drug effects
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Histones / metabolism
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Male
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Phenotype*
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / metabolism
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RNA, Messenger / metabolism
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RNA, Messenger / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, trkB / antagonists & inhibitors
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Reinforcement, Psychology
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Self Administration
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Sex Characteristics
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Sucrose / administration & dosage
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Sweetening Agents / administration & dosage
Substances
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ANA 12 compound
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Azepines
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Benzamides
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Brain-Derived Neurotrophic Factor
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Dopamine Uptake Inhibitors
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Histones
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RNA, Messenger
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Sweetening Agents
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brain-derived growth factor
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Sucrose
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Receptor, trkB
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Cocaine