Actions of methylphenidate on dopaminergic neurons of the ventral midbrain
Abstract
Background Methylphenidate has been suggested to exert its therapeutic effect mainly by blocking the dopamine transporter. In spite of the importance of this interaction, no detailed information is available yet on its actions on single dopaminergic neurons. Methods We examined the effects of methylphenidate on dopaminergic neurons using electrophysiological recordings from rat midbrain slices. Results Methylphenidate inhibited spontaneous firing and caused a membrane hyperpolarization in current clamp or an outward current in voltage clamp. These effects were antagonized by the D(2) receptor antagonist sulpiride. An acute dopamine-depleting treatment of the slices with the dopa-decarboxylase inhibitor carbidopa significantly reduced the effects of methylphenidate. This drug potentiated, in a concentration-dependent manner, cellular responses to exogenous dopamine application. Conclusions Our electrophysiological data are consistent with the hypothesis that methylphenidate inhibits dopamine transporter and suggest that the depression of firing is mediated by the release of newly synthesized dopamine which accumulates extracellularly due to inhibition of its reuptake.
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Methylphenidate directly inhibits dopamine and norepinephrine transporters, has agonist activity at the 5-HT1A receptor, and redistributes VMAT-2.
“The direct effects of MPH include inhibition of the DAT and NET (113, 114, 118, 120, 123, 128), an affinity for and agonist activity at the 5-HT1A receptor (119, 120), and redistribution of VMAT-2 (88, 125).”
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Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria
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Faraone, S. V. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.02.001 · Cited by 631 · see citing works
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- Authors
- Federici, M., Geracitano, R., Bernardi, G., & Mercuri, N. B.
- Affiliations
- Fondazione Santa Lucia (IT)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Mercuri, Nicola B.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2005-02
- Volume
- 57
- Issue
- 4
- Pages
- 361-365
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2032636291
- Cited by
- 48
- References
- 2
- Citations by year
- 2022: 1 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 3 · 2016: 2 · 2014: 1 · 2013: 4 · 2012: 4
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- methylphenidate, dopaminergic neurons, ventral midbrain, dopamine transporter, spontaneous firing, membrane hyperpolarization, dopamine D2 receptor, sulpiride, carbidopa, dopamine depletion, dopamine reuptake
- MeSH terms
- Action Potentials, Central Nervous System Stimulants, Animals, Carbidopa, Cocaine, Dopamine, Dose-Response Relationship, Drug, Drug Interactions, Electric Stimulation, Enzyme Inhibitors, Membrane Potentials, Mesencephalon, Methylphenidate, Neural Inhibition, Neurons, Reserpine, Sulpiride, Dopamine Antagonists, Adrenergic Uptake Inhibitors, Dopamine Uptake Inhibitors, Rats, In Vitro Techniques
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