Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain
Abstract
D- and L-amphetamine sulphate isomers, methylphenidate and atomoxetine, are effective treatments for attention-deficit hyperactivity disorder (ADHD). This study provides a detailed comparison of their effects on the synaptosomal and vesicular accumulation of dopamine (DA) and noradrenaline (NA) and release in vitro in rat prefrontal cortex and striatum. D-amphetamine was more potent than L-amphetamine at inhibiting accumulation of DA or NA in synaptosomes and vesicles. All drugs were weaker at inhibiting the accumulation of vesicular DA and NA compared to synaptosomal accumulation and more potently inhibited NA accumulation than DA. Methylphenidate was weak at inhibiting vesicular accumulation of DA and NA compared to its potent synaptosomal effects. The D-isomer had greater potency than the L-isomer on basal and electrically stimulated striatal DA release; however the L-isomer was 2-fold more potent than the D-isomer on basal fronto-cortical NA release. The selective DA reuptake inhibitor, GBR-12909 and NA reuptake inhibitors, maprotiline and atomoxetine, had different release profiles both on the potency and magnitude of basal and stimulated DA and NA release compared to the amphetamine isomers. These results identify distinct pharmacological action by the amphetamine isomers on dopaminergic and noradrenergic neurotransmission, which may impact on their therapeutic effects in the treatment of ADHD.
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The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity.
“The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function.”
Amphetamine's effect on synaptic dopamine and norepinephrine is mediated by inhibition of dopamine and norepinephrine transporters, reducing reuptake.
“This effect is mediated by inhibition of DA transporters (DAT) and NE transporters (NET) (44, 52, 58), which reduces the reuptake of these molecules from the synapse.”
Amphetamine also inhibits VMAT-2, increasing vesicular dopamine release and causing reverse transport of cytosolic dopamine via DAT.
“AMP also increases vesicular DA release via inhibition of the vesicular monoamine transporter 2 (VMAT-2), which releases DA from vesicular storage, and the concomitant release of cytosolic DA via reverse transport by the DAT (58, 88, 99).”
Methylphenidate elevates extracellular dopamine and norepinephrine levels.
“As a consequence of these interactions, MPH elevates extracellular DA and NE levels (58, 71, 94, 107).”
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References 56 · Cited by 101
- Authors
- Easton, N., Steward, C., Marshall, F., Fone, K., & Marsden, C.
- Affiliations
- University of Nottingham (GB)
- University of Cambridge (GB)
- Corresponding author
- Easton, Neil
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 52
- Issue
- 2
- Pages
- 405-414
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2045118876
- Cited by
- 101
- References
- 56
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 3 · 2019: 6 · 2018: 7 · 2017: 8 · 2016: 7 · 2015: 4 · 2014: 4 · 2013: 7 · 2012: 4
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shire
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- d-amphetamine, L-amphetamine, methylphenidate, atomoxetine, dopamine accumulation, noradrenaline accumulation, synaptic vesicles, synaptosomes, dopamine release, noradrenaline release, prefrontal cortex, striatum, attention deficit hyperactivity disorder, dopamine reuptake inhibitors, norepinephrine reuptake inhibitors, GBR 12909, maprotiline
- MeSH terms
- Atomoxetine Hydrochloride, Animals, Brain, Dopamine, Dose-Response Relationship, Drug, Male, Methylphenidate, Models, Biological, Norepinephrine, Propylamines, Synaptic Vesicles, Synaptosomes, Tritium, Rats, Sprague-Dawley, Adrenergic Agents, Microscopy, Electron, Transmission, Rats
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