Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice
Open accessAbstract
Methylphenidate is a frequently prescribed stimulant for the treatment of attention deficit hyperactivity disorder (ADHD). An important assumption in the animal models that have been employed to study methylphenidate's effects on the brain and behavior is that bioavailability of methylphenidate in the animal models reflects that in human subjects. From this perspective, the dose and route of administration of methylphenidate assume critical importance because both these factors likely influence rate of uptake, plasma and brain concentrations of the drug. In the present study, plasma and brain concentrations of d- and l-methylphenidate and d- and l-ritalinic acid were measured in 2-month old mice (equivalent to young adulthood in humans) following a single oral administration of a racemic mixture. Our data show that oral administration of 0.75 mg/kg dose produced within 15 min, plasma levels of d-methylphenidate that correspond to the clinically effective plasma levels in human subjects (estimated to be 6-10 ng/ml). Brain concentrations of d- and l-methylphenidate tended to exceed their plasma concentrations, while the plasma concentrations of d- and l-ritalinic acid exceeded their brain concentrations. A single oral administration at 0.75 mg/kg dose increased dopamine content of the frontal cortex within 1 h, without producing statistically significant changes in serotonin or noradrenaline contents. Striatal monoamine levels remained unaltered. These data highlight disparities between plasma and brain concentrations of methylphenidate and its metabolites following oral administration and illustrate brain region- and monoamine-specific changes produced by the low oral dose of methylphenidate.
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The increase of IFG/insula activation with methylphenidate is likely mediated by both noradrenergic and dopaminergic mechanisms.
“The increase of IFG/insula activation with methylphenidate is likely mediated by both noradrenergic and dopaminergic mechanisms, given that in frontal regions both in humans 15, 69, 70 and in animals 69, 70 methylphenidate increases noradrenaline equally or more than dopamine via reuptake inhibition of noradrenaline transporters, which clear both catecholamines.”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [69]
The Results report increased frontal-cortex dopamine content in mice after methylphenidate, supporting a dopaminergic effect. The Discussion says noradrenaline showed no significant tissue change and cautions that tissue measurements cannot establish neurotransmitter release. The paper does not assess IFG/insula activation or establish the proposed dual mechanism through noradrenaline transporters. (LLM, conf=0.86)
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- Authors
- Balcioglu, A., Ren, J.-Q., McCarthy, D., Spencer, T. J., Biederman, J., & Bhide, P. G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Bhide, Pradeep G.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 57
- Issue
- 7-8
- Pages
- 687-693
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC2783341
- OpenAlex
- W2038002445
- Cited by
- 60
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 5 · 2012: 2
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (R01DA020796)
- National Institute of Neurological Disorders and Stroke (R01NS043426, P30NS045776)
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- methylphenidate, ritalinic acid, plasma drug concentration, brain drug concentration, oral administration, bioavailability, dopamine, frontal cortex, striatum, attention deficit hyperactivity disorder, mice
- MeSH terms
- Administration, Oral, Central Nervous System Stimulants, Animals, Biological Availability, Brain, Corpus Striatum, Frontal Lobe, Male, Methylphenidate, Plasma, Stereoisomerism, Biogenic Monoamines, Mice
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