Incubation of heroin-seeking behavior and accompanying molecular changes
Open Access
- Author:
- Kuntz-Melcavage, Kara Lynn
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 05, 2008
- Committee Members:
- Kent Eugene Vrana, Dissertation Advisor/Co-Advisor
Kent Eugene Vrana, Committee Chair/Co-Chair
Patricia Sue Grigson Kennedy, Committee Member
Jong Kak Yun, Committee Member
Willard M Freeman, Committee Member
Patricia J Mc Laughlin, Committee Member - Keywords:
- addiction
drug relapse
heroin
opiate - Abstract:
- The field of neuroscience provides an opportunity to combine psychological and biological studies with the ultimate goal of gaining a better understanding of physiological systems. The research presented in this dissertation has used this combinatorial approach to make a contribution to the field of drug abuse, specifically relapse to heroin use. The notion that a handful of genes are particularly important to relapse has guided these studies, expanding on the knowledge that currently exists for cocaine relapse. Incubation of drug-seeking (increased drug-seeking with extended periods of abstinence) is a behavioral model of relapse that has been well-characterized following cocaine self-administration. Data presented in this dissertation demonstrates that incubation also occurs for heroin-seeking behavior and, furthermore, incubation is not limited to drug-seeking behavior, but also extends to goal-directed behavior. Following the behavioral studies, gene expression was assessed in the medial prefrontal cortex and nucleus accumbens using quantitative real-time PCR (QRT-PCR). This study included controls that received non-contingent infusions of heroin at the same time and same dose as the self-administering rats. That is, the rats in this group had no control over the administration of the drug. Additional controls received saline infusions at the same time as self-administering rats received infusions of heroin. The genes that were examined were selected because they had previously been reported to have altered expression following administration of cocaine, morphine, or heroin (in a different behavioral model of heroin use). Prior to sacrifice, rats were reintroduced to the self-administration chambers and allowed to seek drug (although no drug was infused) for 90-minutes. Therefore, the observed gene expression levels were potentially impacted by both heroin abstinence and contextual re-exposure. Five of the twelve genes that were examined were found to be significantly changed, and changes were altered in a time-specific and region-specific manner. Furthermore, in some cases, gene expression was affected differently in rats that self-administered heroin compared to rats that received the same dose and schedule of heroin exposure, but did not self-administer the drug. Examination of gene expression in the medial prefrontal cortex following the 90-min drug-seeking session in the animal model of incubation of heroin-seeking behavior was continued in a microarray experiment. Following a whole genome screen of nearly 41.000 genes, analysis focused on genes that are involved in behavior and neuroplasticity. QRT-PCR was performed for 22 genes identified by the arrays to be significantly changed between the self-administering and yoked saline rats, and 7 of the changes were confirmed. Additionally, 2 other genes that were identified as changed in the microarray experiment have been confirmed in the gene expression work presented elsewhere in this dissertation and in work published by another laboratory. The research in this dissertation demonstrates the similarities between heroin and other drugs of abuse, but also highlights important differences. This material adds to the current knowledge of relapse to drug use by demonstrating that some genes are universally affected following use of either cocaine or heroin. Also, the importance of contingency (i.e., active or passive administration of drug) on gene expression has been demonstrated, a finding that evokes reconsideration of previously published studies. The added understanding of changes in gene expression that occur in a behavioral model of relapse to heroin-seeking behavior helps to narrow the focus of possible “relapse genes” and should be applicable to studies of the broader problem of addiction.