From behavior to epigenetics: Individual differences in heroin addiction
Open Access
- Author:
- Imperio, Caesar Gerald
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 10, 2015
- Committee Members:
- Patricia Sue Grigson Kennedy, Dissertation Advisor/Co-Advisor
Scott C Bunce, Committee Member
Willard M Freeman, Special Member
Robert G Levenson, Committee Member
Victor J Ruiz Velasco, Committee Member - Keywords:
- Addiction
Heroin
Reward
Epigenetics
Enrichment
RNA-seq - Abstract:
- Heroin addiction is a disease of chronic relapse that harms the individual through the devaluation of natural rewards in favor of finding and using drugs. Although destructive, studies have shown that approximately 50% of the human population will transition from controlled heroin use to addiction. Given the variability, there is a need to determine why certain individuals respond differently to heroin. Therefore the goal of this dissertation is to determine at the behavioral and molecular levels why individual differences in addiction-like behavior occur with heroin. In Chapter 2, I developed an animal model that used avoidance of a heroin-paired saccharin cue to stratify rats on their addiction-like behaviors. Greater avoidance of the reward cue was linked with greater drug taking, drug loading, drug escalation, and increased relapse-like behaviors. Using next generation sequencing in Chapter 3, avoidance of the drug-paired taste cue was linked to individual differences in gene expression in the nucleus accumbens. In Chapter 4, I used taste reactivity to assess the perceived hedonic value of the natural reward cue as it came to predict the opportunity to self-administer heroin. Previous cocaine studies have shown that intraoral administration of a drug-paired taste cue elicits negative taste reactivity (gaping) and greater gaping is correlated with greater drug taking behaviors. The results show that, unlike cocaine, intraoral delivery of a heroin-paired taste cue does not support either robust or sustained aversive taste reactivity behavior. Lastly, given the profound effect the environment has on the development of addiction, environmental enrichment was employed to determine if persistent enrichment status can attenuate the development of addiction-like behavior (Chapter 5). Enrichment was shown to attenuate the motivation to work for heroin and prevent drug-seeking behaviors following a period of drug abstinence. Enrichment also buffered the effects of heroin exposure on mRNA expression in the brain. Furthermore, changes in neural DNA methylation were found due to heroin exposure and enrichment status. Taken together, the data presented in this thesis demonstrate the dynamic interplay between an individual’s genetic background and the environment on the development and expression of opiate addiction and associated epigenetic mediators.