Gut and brain profiles that resemble pre-motor and early-stage Parkinson's disease in methamphetamine self-administering rats

Amanda L. Persons, Brinda Desai Bradaric, Leo P. Kelly, Sharanya M. Kousik, Steven M. Graves, Bryan K. Yamamoto, T. Celeste Napier

Research output: Contribution to journalArticlepeer-review


Introduction: Methamphetamine is a potent psychomotor stimulant, and methamphetamine abusers are up to three times more likely to develop Parkinson's disease (PD) later in life. Prodromal PD may involve gut inflammation and the accumulation of toxic proteins that are transported from the enteric nervous system to the central nervous system to mediate, in part, the degeneration of dopaminergic projections. We hypothesized that self-administration of methamphetamine in rats produces a gut and brain profile that mirrors pre-motor and early-stage PD. Methods: Rats self-administered methamphetamine in daily 3 h sessions for two weeks. Motor function was assessed before self-administration, during self-administration and throughout the 56 days of forced abstinence. Assays for pathogenic markers (tyrosine hydroxylase, glial fibrillary acidic protein (GFAP), α-synuclein) were conducted on brain and gut tissue collected at one or 56 days after cessation of methamphetamine self-administration. Results: Motor deficits emerged by day 14 of forced abstinence and progressively worsened up to 56 days of forced abstinence. In the pre-motor stage, we observed increased immunoreactivity for GFAP and α-synuclein within the ganglia of the myenteric plexus in the distal colon. Increased α-synuclein was also observed in the substantia nigra pars compacta. At 56 days, GFAP and α-synuclein normalized in the gut, but the accumulation of nigral α-synuclein persisted, and the dorsolateral striatum exhibited a significant loss of tyrosine hydroxylase. Conclusion: The pre-motor profile is consistent with gut inflammation and gut/brain α-synuclein accumulation associated with prodromal PD and the eventual development of the neurological disease.

Original languageEnglish (US)
Article number108746
JournalDrug and alcohol dependence
StatePublished - Aug 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by NIH R21 ES025920 (TCN and ALP), F31 DA024923 (SMG and TCN), R01 DA042737 (BKY) and the Center for Compulsive Behavior and Addiction at Rush University Medical Center .

Publisher Copyright:
© 2021 Elsevier B.V.


  • Addiction
  • Basal ganglia
  • Dopamine
  • GFAP
  • Stimulant
  • α-synuclein

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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