Heroin addiction is a disease of chronic relapse that harms the individual through devaluation of personal duties and relationships in favor of finding and using drugs. Heroin in particular is disconcerting given its recent rise of use in the United States, and a new study labeling heroin the second most dangerous drug to the user and society [1]. Given the adverse consequences of heroin use, the goal to be drug free holds great importance for the user. Unfortunately, the incidence of relapse is quite high. Thus the question arises: Why do individuals have different relapse outcomes? A number of reports have shown a large interplay between environmental and genetic factors that contribute to the variability in relapse outcomes. Therefore the current proposal will examine how individual differences affect relapse outcome across multiple time periods in Specific Aim 1. Our laboratory has considerable experience in tracking individual differences in sensitivity to drugs of abuse by examining to what extent an animal devalues a drug paired natural reward cue. Rodents that greatly avoid a drug paired natural reward cue display increased motivation to work and take drug [2, 3]. This is the case for a heroin-paired cue as well. Epigenetic differences may contribute to such individual differences in response to drug [4], and DNA methylation, in particular, has been examined as potential factor for relapse given its perceived stability. Nevertheless, current DNA methylation studies have only scratched the surface. No studies, to our knowledge, have examined the DNA methylation differences in rats that respond differently to heroin or determined whether these changes are truly permanent during abstinence.
Specific Aim 3, then, will use the rats from Specific Aim 1 to determine whether differential responding to heroin is linked to differences in DNA methylation in brain. Finally, the learning and memory field has shown that environmental enrichment can alter the epigenetic the landscape and our data [5], and those of others [6-9], have shown that enrichment can protect against addiction-like behaviors. Therefore, a next step is to determine if enrichment status can protect a rat from not only drug-induced reinstatement (Specific Aim 2), but also the accompanying epigenetic changes.
Specific Aim 3 will use the brains from rats from Specific Aim 2 to address this question. In collaboration with the Freeman laboratory, we recently developed a novel next generation sequencing approach to loci-specific DNA methylation analysis and obtained pilot data linking increased responsiveness to heroin in the model with a distinct hippocampal DNA methylation prolife. From this gap in knowledge, I seek to understand how an individual's response to heroin affects abstinence and relapse and link these individual differences in vulnerability with DNA methylation.

Public Health Relevance

Drug relapse is a major concern for heroin addiction creating a relentless cycle of drug use and abstinence. That said, some individuals relapse, while others do not. Understanding the individual heroin-induced adaptions that contribute to relapse is a prime target for novel interventions. In this proposal, I will track individual differences in the propensity to relapse across a range of abstinence periods, both behaviorally and at the epigenetic level, and I will test whether environmental enrichment can ameliorate these changes.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Sorensen, Roger
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Pennsylvania State University
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Imperio, Caesar G; McFalls, Ashley J; Hadad, Niran et al. (2018) Exposure to environmental enrichment attenuates addiction-like behavior and alters molecular effects of heroin self-administration in rats. Neuropharmacology 139:26-40
Imperio, Caesar G; McFalls, Ashley J; Colechio, Elizabeth M et al. (2016) Assessment of individual differences in the rat nucleus accumbens transcriptome following taste-heroin extended access. Brain Res Bull 123:71-80
McFalls, Ashley J; Imperio, Caesar G; Bixler, Georgina et al. (2016) Reward devaluation and heroin escalation is associated with differential expression of CRF signaling genes. Brain Res Bull 123:81-93
Imperio, Caesar G; Grigson, Patricia S (2015) Greater avoidance of a heroin-paired taste cue is associated with greater escalation of heroin self-administration in rats. Behav Neurosci 129:380-8