Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies
Abstract
Methylphenidate is the most commonly prescribed drug for the treatment of ADHD. We have used positron emission tomography to assess the role that methylphenidate's effects in brain dopamine have on its therapeutic and reinforcing effects. We have documented that in the human brain therapeutic doses of methylphenidate block more than 50% of the dopamine transporters and significantly enhance extracellular DA, an effect that appears to be modulated by the rate of DA release. Thus, we postulate that methylphenidate's therapeutic effects are in part due to amplification of DA signals, that variability in responses is in part due to differences in DA tone and that methylphenidate's effects are context dependent. Methylphenidate-induced increases in DA are also associated with its reinforcing effects but only when this occurs rapidly, as with intravenous administration. Moreover, abuse of methylphenidate is constrained by its long half-life, which we postulate limits the frequency at which it can be administered.
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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 [171]
In PET imaging studies, therapeutic doses of stimulant medications increase endogenous DA stimulation of D2 receptors in the striatum.
“Positron-emission tomography imaging studies have shown that therapeutic doses of stimulant medications increase endogenous DA stimulation of D2 receptors in the striatum (132)”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [132]
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References 72 · Cited by 217
- Authors
- Volkow, N.
- Affiliations
- Brookhaven National Laboratory (US)
- Corresponding author
- Volkow, N
- ORCID
- Volkow, N
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 12
- Issue
- 6
- Pages
- 557-566
- ISSN
- 0924-977X (ISSN-L)
- OpenAlex
- W2012137739
- Cited by
- 217
- References
- 72
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 14 · 2014: 14 · 2013: 6 · 2012: 8
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01da009490-08)
- National Institute on Drug Abuse (DA-06891, DA-09490, DA-06278, R01DA006278, R01DA006891)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- methylphenidate, dopamine, dopamine transporter, attention deficit hyperactivity disorder, drug reinforcement, therapeutic effects, dopamine release, extracellular dopamine, abuse liability, intravenous administration, elimination half-life, context sensitivity
- MeSH terms
- Animals, Attention Deficit Disorder with Hyperactivity, Brain, Dopamine, Humans, Membrane Glycoproteins, Methylphenidate, Nerve Tissue Proteins, Reinforcement, Psychology, Tomography, Emission-Computed, Dopamine Uptake Inhibitors, Substance-Related Disorders, Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins
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