Project Summary/Abstract
Drug addiction is a complex brain disorder that takes an enormous toll on individual and economic health. Current
drug-abuse treatments are not effective in all individuals, and many recovering addicts continue to relapse. Drug
exposure usurps normal reward circuit function, including the connections between the ventral tegmental area
(VTA) and the nucleus accumbens (NAc). Both NAc and VTA undergo molecular and physiological changes in
response to drugs of abuse. The VTA sends dopaminergic projections to the NAc, and the NAc sends GABAergic
projections back to the VTA. Activity in NAc and VTA are key for driving drug use and are heavily implicated in
drug relapse. Numerous studies have established the importance of the dopaminergic VTA to NAc projection,
however the connection from NAc back to VTA is understudied in drug addiction.
The incidence of opioid use, opioid addiction, and death from opioid overdose are at an unprecedented high. In
this K99/R00 Pathway to Independence Award, I aim to identify how NAc projections to the VTA influence opioid
use and relapse. Using a mouse model of fentanyl self-administration, I have collected preliminary data showing
NAc neurons that project to VTA control fentanyl seeking after forced abstinence. In this study, I intend to utilize
intersectional circuit manipulation and cutting-edge molecular biology to investigate the molecular mechanisms
by which NAc projections to VTA control fentanyl intake and relapse. During the mentored phase, in Aim 1, I will
learn operant self-administration procedures and combine them with chemogenetic manipulation to assess the
necessity of NAc terminals in VTA in fentanyl use and relapse. In Aim 2, I will learn RNAseq and in situ
hybridization to profile molecular adaptations in specific VTA neurons after fentanyl self-administration. During
the independent phase, in Aim 3, I will use novel viral constructs to assess the role of molecular manipulations
in specific VTA neurons in fentanyl use and relapse. In Aim 4, I will assess the role of fentanyl and molecular
manipulations on dopamine release in the NAc using fast-scan cyclic voltammetry. Together, the research
proposed in this Pathway to Independence Award will elucidate molecular mechanisms in the NAc-VTA circuit
driving opioid use and relapse, while simultaneously providing me with the tools necessary for establishing an
independent research program that bridges molecular biology, circuit manipulation, operant behavior, and
voltammetry for examining addiction.