PROJECT SUMMARY / ABSTRACT
In the height of the opioid crisis in our country, deaths from methamphetamine (METH) overdose are on the
rise, and there is no FDA-approved medication for METH use disorder (MUD). New drug targets are needed,
particularly for people who heavily use the drug because they have the most difficulty quitting METH use, suffer
from a variety of serious neurological problems, and are at high risk to overdose on the drug. Our work with a rat
model of heavy compulsive METH consumption (severe MUD) provided evidence that overexpression of
neuroprotective protein parkin in the nucleus accumbens (NAc), a key reward-mediating brain area, plays a role
in severe MUD. Parkin is a protein-ubiquitin ligase known to play a critical role in maintaining mitochondrial health
and, therefore, in maintaining generation of cellular energy - adenosine triphosphate (ATP). Our preliminary
proteomic data shows that upregulation of parkin in the NAc leads to upregulation of several Krebs cycle
enzymes whereas parkin knockout leads to their downregulation. Dysfunctional mitochondria are the known
consequence of METH use. This proposal investigates the novel hypothesis that parkin decreases METH
cravings and addictive behaviors by the Krebs cycle function in the NAc from METH neurotoxicity. This
helps to maintain ATP generation in METH-exposed NAc neurons, which otherwise would be impaired by METH-
induced oxidative stress. In other words, we will test whether dysfunctional mitochondria are a cause of MUD.
We will test the hypothesis by three independent specific aims. The specific aim 1 will establish whether and
how parkin protects Krebs cycle function in rat NAc from neurotoxicity of self-administered METH. The specific
aim 2 will determine whether parkin overexpression in the NAc of rats with developed severe MUD will decrease
METH addictive behaviors. The specific aim 3 will determine whether overexpression of oxidative stress-
sensitive Krebs cycle enzyme DLST (dihydrolipoamide S-succinyl-transferase) in the NAc of rats with developed
severe MUD will decrease METH addictive behaviors. Given that parkin may serve a dual function of decreasing
METH neurotoxicity and METH cravings, these studies will determine whether targeting parkin has a significant
therapeutic potential in severe MUD. Given the limited indirect data suggesting that METH neurotoxicity in NAc
mitochondria contributes to development of MUD, these studies will provide clarity about the role of METH-
induced oxidative stress in mediating METH use and in development of motivation to seek METH during
abstinence. Furthermore, the results will benefit opioid and alcohol use disorder research as these disorders
induce mitochondrial dysfunction. Lastly, since chronic use of METH, particularly at high doses, predisposes to
development of Parkinson’s disease and potentially also to Alzheimer’s disease, the results from this research
will add information to these research areas.