Methylphenidate affects task-switching and neural signaling in non-human primates
Open accessAbstract
Rationale Low doses of psychostimulants such as methylphenidate (MPH), which increase extracellular dopamine and norepinephrine by inhibiting their reuptake, are the most commonly used treatment for attention deficit hyperactivity disorder (ADHD). Therapeutic doses of these drugs may improve focused attention at the expense of hindering other cognitive functions, including the ability to adapt behavior in response to changing circumstances-cognitive flexibility. Cognitive flexibility is thought to depend on proper operation of the prefrontal cortex (PFC) and is also linked to reward processing, which is dopamine-dependent. Additionally, reward outcome signals have been recorded from the PFC.Objectives This study tested the hypothesis that therapeutic doses of MPH impair cognitive flexibility and that this impairment in performance resulted from interference in reward signals within the PFC.Methods Four rhesus monkeys were given therapeutically relevant doses of oral MPH (0, 3, and 6 mg/kg) while performing an oculomotor switching task to evaluate its effect on task performance. Single-unit recordings in the PFC of two monkeys were taken before and after MPH administration during task performance.Results The results show that MPH does hinder switching task performance, an effect that was correlated with a reduction in the amplitude of outcome signals found in the discharges of some neurons in the PFC.Conclusions Methylphenidate impaired task-switching performance, which can be used as a measure of cognitive flexibility. This detriment may result from degraded outcome signaling within the PFC. This study has implications for the use of MPH in the treatment of ADHD.
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MPH exerts its action promoting the downregulation of DAT and NET, leading to an increase of DA and NE levels in the prefrontal cortex that control hyperactivity and deficits in inhibitory behaviour.
“MPH exerts its action promoting the downregulation of DA and NE transporter (DAT and NET) (protein targets) [139]. This leads to an increase of DA and NE levels in the prefrontal cortex (synaptic cleft) that control hyperactivity and deficits in inhibitory behaviour (improvement in attentional deficit and cognitive functioning) [139, 171].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [139]
The Introduction states that MPH blocks DAT and NET, increasing extracellular dopamine and norepinephrine, and that low doses improve focused attention. It does not describe transporter downregulation. The Discussion says that, in non-human primates, increased dopamine was documented in the striatum and caudate, not the PFC; it also does not establish that the proposed PFC increase controls hyperactivity or inhibitory-behaviour deficits. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMPH acts as an inhibitor of NET (SLC6A2).
“and NET (SLC6A2) [139]”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [139]
MPH acts as an inhibitor of DAT (SLC6A3).
“it acts as an inhibitor of DAT (SLC6A3) [139]”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [139]
Evidence from rhesus monkeys given therapeutic doses of methylphenidate suggests the drug can impair task-switching performance, indicating improved attention may come at the expense of flexibility.
“There is some evidence from studies of rhesus monkeys given therapeutic doses of methylphenidate that the drug can impair task-switching performance. This indicates that the improved ability to focus attention may come at the expense of hindering flexibility110.”
From Cognitive and behavioural flexibility: Neural mechanisms and clinical considerations (2021) · cites this paper as [110]
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Cognitive and behavioural flexibility: Neural mechanisms and clinical considerations
Uddin, L. Q. (2021) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00428-w · Cited by 698 · see citing works
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- Authors
- Rajala, A. Z., Populin, L. C., & Jenison, R. L.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Jenison, Rick L
- Venue
- Psychopharmacology
- Published
- 2020-02-18
- Volume
- 237
- Issue
- 5
- Pages
- 1533-1543
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC7196524
- OpenAlex
- W3007171987
- Cited by
- 13
- References
- 58
- Citations by year
- 2025: 3 · 2023: 4 · 2022: 2 · 2021: 3 · 2019: 1
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AA018736, DC003693)
- National Science Foundation (IOB-051458)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- methylphenidate, task switching, cognitive flexibility, prefrontal cortex, dopamine, norepinephrine, psychostimulants, attention deficit hyperactivity disorder, single-unit recording, rhesus monkeys, adverse drug reactions
- MeSH terms
- Central Nervous System Stimulants, Animals, Attention, Attention Deficit Disorder with Hyperactivity, Cognition, Dose-Response Relationship, Drug, Macaca mulatta, Male, Methylphenidate, Psychomotor Performance, Signal Transduction, Prefrontal Cortex, Dopamine Uptake Inhibitors
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