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Cited by 102Parkinson's Disease Mechanisms and TreatmentsNeurotransmitter Receptor Influence on BehaviorNeuroinflammation and Neurodegeneration Mechanisms

Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice

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Sadasivan, Shankar, Pond, Brooks B., Pani, Amar K., Qu, Chunxu, Jiao, Yun, Smeyne, Richard J.·2012·PLoS ONE
DOI 10.1371/journal.pone.0033693PMC PMC3312333
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Abstract

BACKGROUND: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a "cognitive enhancer" and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. METHODOLOGY/PRINCIPAL FINDINGS: Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing. CONCLUSION: Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.

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  • Long-term use of MPH induces DA neuron loss and microglia activation causing an increase in pro-inflammatory markers TNFα and IL-1β, resulting in activation of neuroinflammation and triggering a neurodegenerative process.

    “Several studies have exposed that the long-term use of MPH induces the DA neuron loss and microglia activation causing an increase in pro-inflammatory markers TNFα and IL-1β, among others, resulting in the activation of neuroinflammation and triggering a neurodegenerative process [192, 193].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [192]

    The Discussion reports that chronic 10 mg/kg MPH caused a small but significant loss of dopamine neurons in mice, and the Results report increased activated microglia at that dose. But the Results found increased TNFα and IL-6 expression only after an acute dose; the Discussion explicitly says inflammatory gene expression did not increase after chronic administration. IL-1β was examined but is not reported as increased, and the proposed link between inflammation and neuronal loss is a hypothesis rather than an established causal chain. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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Authors
Sadasivan, S., Pond, B. B., Pani, A. K., Qu, C., Jiao, Y., & Smeyne, R. J.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • East Tennessee State University (US)
Corresponding author
Smeyne, Richard J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-03-21
Volume
7
Issue
3
Pages
e33693
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0033693
PMC
PMC3312333
OpenAlex
W2029604167
Cited by
102
References
7
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 14 · 2015: 14 · 2014: 8 · 2013: 7 · 2012: 2
FWCI
6.48
Type
journal article
Language
en
Update notices
correction (2012-05-08)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
American Lebanese Syrian Associated Charities
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
methylphenidate, dopamine neuron loss, substantia nigra pars compacta, microglial activation, basal ganglia, neurodegeneration, dopamine transporter, gene expression profiling, glial cell line-derived neurotrophic factor, thymidine phosphorylase, interleukin-6, TNF-α, striatum
MeSH terms
Central Nervous System Stimulants, Animals, Basal Ganglia, Methylphenidate, Substantia Nigra, Tumor Necrosis Factor-alpha, Interleukin-6, Microglia, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Dopamine Plasma Membrane Transport Proteins, Vesicular Monoamine Transport Proteins, Glial Cell Line-Derived Neurotrophic Factor, Mice, Dopaminergic Neurons

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