Many studies demonstrate that the hereditary nature of drug abuse is due to both genetic and environmental factors. One mechanism regulating interactions between genes and the environment are epigenetic modifications. In this context, the term epigenetics refers to DNA and histone protein modifications that regulate gene expression and which are transmitted from a mother cell to a daughter cell, or from a parent to its progeny, but which do not change the underlying DNA sequence. While it is clear that epigenetic modifications can be passed from one generation to the next, the mechanisms involved in the transmission of these effects are not fully understood. Several recent findings indicate that the maternal environment, both pre- and postnatal, may play a critical role in epigenetic transfer. To date, the role of epigenetics in familial patterns of drug abuse has not been well-studied. We have developed an animal model of adolescent morphine exposure in female rats to examine the long-term consequences of opiate use during this unique developmental period. Our findings demonstrate that, in addition to significant alterations in gene expression in adult female rats exposed to morphine during adolescence, the offspring of adolescent-exposed females demonstrate enhanced responsiveness to morphine. One important aspect of this model is that adolescent morphine- exposed females are drug-free for several weeks prior to mating, and thus there is no direct in utero exposure. The purpose of this proposal is to develop, refine, and implement non-surgical embryo transfer in females exposed to morphine during adolescent development. This technique will then be used to delineate offspring effects that are directly mediated by modifications at the level of the embryo from those induced by alterations in the pre- and/or postnatal environment. The primary focus will be on transgenerational alterations in morphine sensitivity (behavioral and physiological) as these effects are well-characterized. Moreover, understanding how drug-induced alterations in morphine sensitivity may be passed from one generation to the next may help identify basic mechanisms underlying familial patterns of substance use.

Public Health Relevance

The use and misuse of opiates in female adolescent populations has increased dramatically in the past decade. Using a rat model, we have observed significant transgenerational effects of female adolescent opiate exposure. The use of embryo transfer will help delineate how these effects are transmitted from mother to offspring. These findings will both enhance our understanding of the long-term impact of opiate use in this population and begin to identify mechanisms underlying familial patterns of substance use.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Research Grants (R03)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Satterlee, John S
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Tufts University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Vassoler, Fair M; Toorie, Anika M; Byrnes, Elizabeth M (2018) Transgenerational blunting of morphine-induced corticosterone secretion is associated with dysregulated gene expression in male offspring. Brain Res 1679:19-25
Vassoler, Fair M; Oliver, David J; Wyse, Cristina et al. (2017) Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure. Neuropharmacology 113:271-280
Vassoler, Fair M; Wright, Siobhan J; Byrnes, Elizabeth M (2016) Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring. Neuropharmacology 103:112-21
Vassoler, F M; Byrnes, E M; Pierce, R C (2014) The impact of exposure to addictive drugs on future generations: Physiological and behavioral effects. Neuropharmacology 76 Pt B:269-75