# Chronic methamphetamine-induced catecholaminergic degeneration and cognitive dysfunction

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2022 · $43,290

## Abstract

PROJECT SUMMARY/ABSTRACT
Methamphetamine (meth) is a powerfully addictive psychostimulant capable of causing neuronal damage.
Recent studies by my mentor, Dr. Graves, found that meth increases mitochondrial stress in the axons of
substantia nigra pars compacta (SNc) dopamine (DA) neurons resulting from MAO metabolism of cytosolic DA.
Pilot studies showed similar effects in the axons of Locus coeruleus (LC) norepinephrine (NE) neurons. Using
a 28-day meth administration paradigm, recent studies by Dr. Graves found degeneration of SNc DA neurons
and that pharmacological inhibition of MAO was neuroprotective. Pilot studies similarly show chronic meth-
induced LC degeneration that is attenuated by MAO inhibition. These data suggest that axonal MAO-
dependent mitochondrial stress contributes to chronic meth-induced degeneration. The overarching goal of
this proposal is to determine the progression and presentation of degeneration, whether neuronal (as opposed
to astrocytic) MAO enzymes are necessary for degeneration, and the behavioral consequences of chronic
meth-induced SNc and LC degeneration. My central hypothesis is that chronic meth induces a neuronal
MAO-dependent dying-back pattern of SNc and LC degeneration resulting in cognitive impairment and
will be tested in the following aims: Aim 1: Determine if chronic meth produces a dying-back pattern of SNc
and LC degeneration. Meth increases axonal, but not somatic MAO-dependent mitochondrial stress, and MAO
inhibition prevented chronic meth-induced SNc and LC degeneration; these data suggest that MAO-dependent
axonal mitochondrial stress drives degeneration. I therefore hypothesize that chronic meth will produce a
dying-back pattern of SNc and LC degeneration, where axonal loss precedes somatic loss. Aim 2: Determine
if neuronal MAO is necessary for chronic meth-induced SNc and LC degeneration. Studies show systemic
MAO inhibition prevented chronic meth-induced SNc and LC degeneration, but MAO enzymes are expressed
in neurons and astrocytes. Given that meth increased mitochondrial stress in SNc and LC axons, I hypothesize
that neuronal MAO is necessary for degeneration. Aim 3: Determine the behavioral consequences of chronic
meth-induced SNc and LC degeneration. SNc degeneration and LC lesioning are associated with impairments
in novel object recognition and context-associated fear conditioning assays, respectively; I therefore
hypothesize that chronic meth-induced degeneration of the SNc and LC will lead to similar behavioral
impairments. I will test my hypotheses by training in and using immunofluorescence, unbiased stereological
assessment of neuronal and axonal degeneration, behavioral analysis, and both genetic and pharmacological
inhibition of MAO enzymes. Testing my hypotheses will provide me with outstanding technical and conceptual
training as a research scientist. Completion of proposed aims will improve our understanding of the
neurodegenerative consequences of chronic meth, expanding k...

## Key facts

- **NIH application ID:** 10464353
- **Project number:** 1F31DA054779-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Alexander N Pilski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,290
- **Award type:** 1
- **Project period:** 2022-01-14 → 2025-01-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464353

## Citation

> US National Institutes of Health, RePORTER application 10464353, Chronic methamphetamine-induced catecholaminergic degeneration and cognitive dysfunction (1F31DA054779-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10464353. Licensed CC0.

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