Intersecting genetic risk for extreme cocaine self-administration with dopamine neurotransmission

Project summary/abstract
Cocaine use disorder is a complexly determined, heritable trait that imposes significant harm on those afflicted
and on society. Discovery of the genetic factors that influence cocaine use disorder risk is imperative for a
comprehensive understanding of cocaine addiction neurobiology. In an ongoing study, we have characterized
a large panel of inbred mouse lines for voluntary cocaine self-administration (IVSA). We are utilizing this
approach to identify genes and allelic variants that influence cocaine self-administration, including Neuron-
navigator-1 (Nav1), which has emerged as a candidate gene from our genetic analyses. Furthermore, inbred
reference strains in the HMDP that are predisposed to take large amounts of cocaine represent polygenic
models of extreme cocaine use and can be used to understand how risk variants collectively impact
neurobiology to ultimately affect cocaine self-administration. The project proposed here will directly investigate
the polygenic and single gene impact of genetic risk for extreme cocaine IVSA on mesolimbic dopamine
neurotransmission, a key neurobiological function impacted by cocaine and other drugs of abuse. This project
will provide training in fast-scan cyclic voltammetry, optogenetics and fiber photometry and will allow me to
create a unique niche in addiction neurogenetics research. Aim 1 will investigate the influence of polygenic risk
for extreme cocaine IVSA on dopamine neurotransmission in the Nucleus Accumbens (NAc) shell after acute
application of cocaine. This aim may reveal genetic influences on basal and acute dopamine responses that
underlie risk for dysregulated cocaine use. Aim 2 will investigate the influence of polygenic risk for extreme
cocaine IVSA on neuroadaptations in dopamine transmission in the NAc following chronic cocaine IVSA
exposure. This aim may reveal genetically determined adaptations of dopamine transmission that underlie
escalated use after chronic exposure. Aim 3 will evaluate the causal effects of experimental changes in Nav1
expression on dopamine transmission at the single-gene level. This project will advance understanding of how
genetics intersect with neurobiology to affect cocaine use. The training I will receive in conducting this project
will broaden my skill set and allow me to more effectively investigate addiction neurogenetics.

Grant Number: 5R00DA055091-03
NIH Institute/Center: NIH
Principal Investigator: Jared Bagley