Abstract
Paternal cocaine use causes phenotypic alterations in offspring behavior and associated neural processing. In rodents, changes in first generation (F1) offspring include drug reward behavior, circadian timing, and anxiety responses. This study, utilizing a murine (C57BL/6J) oral cocaine model, examines the effects of paternal cocaine exposure on fundamental characteristics of offspring reward responses, including: 1) the extent of cocaine-induced effects after different durations of sire drug withdrawal; 2) sex- and drug-dependent differences in F1 reward preference; 3) effects on second generation (F2) cocaine preference; and 4) corresponding changes in reward area (nucleus accumbens) mRNA expression. We demonstrate that paternal cocaine intake over a single ˜40-day spermatogenic cycle significantly decreased cocaine (but not ethanol or sucrose) preference in a sex-specific manner in F1 mice from sires mated 24 h after drug withdrawal. However, F1 offspring of sires bred 4 months after withdrawal did not exhibit altered cocaine preference. Altered cocaine preference also was not observed in F2′s. RNASeq analyses of F1 accumbens tissue revealed changes in gene expression in male offspring of cocaine-exposed sires, including many genes not previously linked to cocaine addiction. Enrichment analyses highlight genes linked to CNS development, synaptic signaling, extracellular matrix, and immune function. Expression correlation analyses identified a novel target, Fam19a4, that may negatively regulate many genes in the accumbens, including genes already identified in addiction. Collectively, these results reveal that paternal cocaine effects in F1 offspring may involve temporally limited epigenetic germline effects and identify new genetic targets for addiction research.
| Original language | English |
|---|---|
| Pages (from-to) | 68-81 |
| Number of pages | 14 |
| Journal | Behavioural Brain Research |
| Volume | 367 |
| DOIs | |
| State | Published - Jul 23 2019 |
Funding
This manuscript has been partially authored by UT-Battelle, LLC under Contract No. DE-AC05- 00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ). All other authors have nothing to disclose. The authors would like to acknowledge undergraduate students Robert Woodruff, Victoria Shaker, Alayna Stroberg, Leeann Ray and Jerika Schirf for their assistance in animal husbandry and consumption measurements. We would also like to thank the Kent State UniversityDepartment of Biological Sciences, Kent State University of Biomedical Sciences, and the University of Tennessee Knoxville Department of Biochemistry & Cellular and Molecular Biology for funding. This research used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05-00OR22725.
| Funders | Funder number |
|---|---|
| Kent State University Department of Biological Sciences | |
| Kent State University of Biomedical Sciences | |
| University of Tennessee Knoxville Department of Biochemistry & Cellular and Molecular Biology | |
| U.S. Department of Energy | |
| Office of Science | |
| Kent State University |
Keywords
- Drug reward
- Fam19a4
- Generational inheritance
- Oral cocaine
- RNASeq
- Transgenerational inheritance
