Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder

Abstract

There is no FDA-approved medication for methamphetamine (METH) use disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH use disorder. PARKIN knockout, PARKIN-overexpressing, and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying “resilience” or vulnerability to METH use disorder and identify PARKIN as a novel potential drug target to treat heavy use of METH.

Methamphetamine exposure increases cardiac microvascular permeability by activating the VEGF-PI3K-Akt-eNOS signaling pathway, reversed by Bevacizumab

“…METH is an extremely dangerous substance, widely regarded as the most poisonous and addictive, 26 because it stimulates 10 times the normal amount of dopamine production and causes considerable harm. 27 METH induces cardiac injury by multifactorial pathways, according to a growing number of studies published in the previous few years.…”

Breaking the Chains: Advances in Substance Addiction Research through Single-Cell Sequencing, Epigenetics, and Epitranscriptomic

“…Sharma et al showed that studying the neuronal substrates underlying "resilience" or vulnerability to METH use disorder can be facilitated by using rats with excess or deficit PARKIN. Additionally, PARKIN may be a novel therapeutic target for the treatment of METH use disorder [154]. After METH withdrawal, protein ubiquitination and E3 ubiquitin ligases are increased in the central amygdala.…”

Epigenetic mechanisms involved in methamphetamine addiction

“…Parkin increases the ubiquitination of substrate proteins to enhance their degradation. Parkin activity is associated with METH addiction in rats (Sharma et al, 2021). Protein ubiquitination and E3 ubiquitin ligases are increased in the central amygdala (CeA) after METH withdrawal.…”