Neurodegeneration and behavior in rodents treated with chronic methamphetamine

Abstract

Thirty million people globally used amphetamine-type stimulants in 2022; while in the United States, 2.7 million people over the age of twelve reported using methamphetamine (meth) that same year. Meth is a powerful psychostimulant with a high propensity for abuse. The number of people using meth has been steadily increasing over the past decade alongside increases in meth-related hospitalizations, overdose deaths, and the number of individuals suffering from a meth-use disorder (MUD). Beyond being highly addictive, studies on individuals with a MUD have demonstrated that meth abuse can result in neurotoxicity alongside cognitive impairment. There are currently no treatments for either MUD or meth-induced neurotoxicity. Meth has recently been shown to cause a monoamine oxidase (MAO)-dependent increase of mitochondrial oxidative stress in catecholaminergic substantia nigra pars compacta (SNc) dopamine and locus coeruleus (LC) norepinephrine axons. Moreover, it has been demonstrated that applying chronic meth treatment (28 days of 5mg/kg injections once per day) results in degeneration of SNc and LC neurons and axons, and pre-treatment using an MAO isoform B inhibitor or mitochondrial antioxidant during meth administration prevents degeneration. These results demonstrate that meth-induced MAO-dependent mitochondrial oxidative stress in catecholaminergic axons is necessary for degeneration of SNc or LC neurons and axons following 28 days of meth administration. While it was shown that SNc cell loss does not occur after 14 days of this meth treatment regimen, it is unclear whether axon loss begins at this point and whether axonal loss precedes somatic loss in these regions. Additionally, while chronic meth use in humans is correlated with cognitive impairment, it is unclear if chronic meth-induced degeneration in rodent models results in behavioral deficits. My thesis work here, building on clinical and pre-clinical research of meth-induced catecholaminergic neurotoxicity and degeneration that has been carried out up to this point (Chapter 1), for the first time, demonstrates that chronic meth treatment results in SNc and LC axon loss prior to somatic degeneration in male mice and that pre-treatment with MAO isoform A and B inhibitor phenelzine is neuroprotective, while female mice are resistant to catecholaminergic degeneration (Chapter 2). Then, I show that chronic meth administration, which causes SNc and LC degeneration, does not result in novel object recognition or fear memory deficits in male mice but does cause reduced locomotion in both male and female mice (Chapter 3). Finally, I discuss my findings (Chapter 4) within the context of prior meth neurotoxicity literature, expand on the sex differences noted in Chapter 2, and examine links between chronic meth-induced neurodegeneration and neurodegenerative disorders.