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Grants and Contracts Details
Description
Misuse of opioids represents a substantial public and economic burden in the US and worldwide. The existing
pharmacological approaches to treatment of opioid use disorder (OUD) are most efficacious when coupled with
behavioral therapies that target individual triggers to reduce or eliminate excessive drug consumption. While
individual variability in opioid use have been acknowledged repeatedly in animal behavioral models, the
genomic markers linked to neurobiological adaptations underlying such variability are not well understood. We
argue that understanding the molecular background of individual differences in behavioral vulnerability to
opioid use is critical for development of personalized pharmacogenomic approaches for OUD that may
replicate clinical success of personalized cancer treatments. In line with this argument, we hypothesize that
individual behavioral variability in escalation of fentanyl use is linked to systems level variability of
genomic and functional networks within in the nucleus accumbens and prefrontal cortex. Escalation of
drug intake is a central component of OUD diagnosis that can be modeled in animals trained to self-administer
opioids under extended access conditions. Based on the published literature and preliminary data, we propose
three complementary Aims to monitor development of escalated intake at behavioral, functional
cellular/network, and genomic levels of analysis. Our Aim 1 hypothesizes that escalation of fentanyl intake
emerges on the background of individual differences in sensitivity to non-drug (sucrose) reward. Finding
evidence to support this aim has the potential to identify vulnerable individuals prior to initiation of opioid use.
Aim 2 examines neuronal outcomes associated with escalated fentanyl intake. Specifically, we will evaluate
whether individual profiles of escalated intake reflect altered regulation of cell excitability by four potassium
channel families and the impact on neuronal output at single cell and network levels. The data collected as part
of this aim will establish functional, neuronal drivers of vulnerability to escalated intake. Finally, Aim 3
compares the genomic landscape underlying variable fentanyl escalation in laboratory animals (rats) to human
opioid use databases. In this aim, we take advantage of cell-type specific RNA sequencing to evaluate both
neuronal and non-neuronal mechanisms of escalated intake in the nucleus accumbens and prefrontal cortex.
This aim is expected to identify novel molecular pathways linked to fentanyl escalation and test the
translational relevance of our preclinical findings to a human sample. To characterize interactions at the
behavioral, functional, and genomic levels of analysis, a unifying statistical framework is developed based on
linear mixed models to examine the strength of bi-directional relationships between behavioral escalation of
intake and molecular outcomes.
Status | Active |
---|---|
Effective start/end date | 3/15/21 → 12/31/25 |
Funding
- National Institute on Drug Abuse
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Projects
- 1 Active
-
Functional and Genomic Signatures of Escalated Fentanyl Use
Turner, J., Bumgardner, V., Charnigo, R., Bardo, M. & Ortinski, P.
National Institute on Drug Abuse
3/15/21 → 12/31/25
Project: Research project