Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine
Abstract
Methylphenidate (MP) and amphetamine (AMP) are first-line treatments for attention-deficit hyperactivity disorder. Although both drugs have similar therapeutic potencies, the stimulatory effect of AMP on extracellular dopamine (ECF DA) is greater than that of MP. We compared extracellular effects directly against synaptic changes. ECF DA was assessed by microdialysis in freely moving rodents and synaptic dopamine (DA) was measured using PET and [11C]-raclopride displacement in rodents and baboons. Microdialysis data demonstrated that MP (5.0 mg/kg, i.p.) increased ECF DA 360% +/- 31% in striatum, which was significantly less than that by AMP (2.5 mg/kg, i.p.; 1398% +/- 272%). This fourfold difference was not reflected by changes in synaptic DA. In fact, rodent PET studies showed no difference in striatal [11C]-raclopride binding induced by AMP (2.5 mg/kg, i.p.; 25% +/- 4% reduction) compared with that by MP (5.0 mg/kg, i.p.; 21% +/- 4% reduction). Primate PET experiments also showed no differences between AMP (0.5 mg/kg, i.v.; 24% +/- 4% reduction) and MP (1.0 mg/kg, i.v.; 25% +/- 7% reduction) induced changes in [11C]-raclopride binding potential. The similar potencies of MP and AMP to alter synaptic DA, despite their different potencies in raising ECF DA, could reflect their different molecular mechanisms.
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Methylphenidate elevates extracellular dopamine and norepinephrine levels.
“As a consequence of these interactions, MPH elevates extracellular DA and NE levels (58, 71, 94, 107).”
MPH preferentially blocks the reuptake of catecholamines, including dopamine and norepinephrine, in both the striatum and prefrontal cortex.
“a psychostimulant that preferentially blocks the reuptake of catecholamines, including dopamine (DA) and norepinephrine (NE), in both the striatum and prefrontal cortex (Mehta et al., 2000, 2004; Schiffer et al., 2006; Heal et al., 2009).”
From The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD (2015) · cites this paper as Schiffer et al., 2006
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“…may blunt psychostimulant-induced increases in DA, and this effect may be particularly sensitive to comparisons between microdialysis and PET data (Breier et al., 1997; Butcher et al., 1991; Di Chiara and Imperato, 1988; Drevets et al., 1999; Guix et al., 1992; Hurd et al., 1998; Hurd and…”
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The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD
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- Authors
- Schiffer, W. K., Volkow, N. D., Fowler, J. S., Alexoff, D. L., Logan, J., & Dewey, S. L.
- Affiliations
- Brookhaven National Laboratory (US)
- National Institute on Drug Abuse (US)
- Corresponding author
- Schiffer, W.K.
- Venue
- Synapse
- Publisher
- Wiley
- Published
- 2005-12-29
- Volume
- 59
- Issue
- 4
- Pages
- 243-251
- ISSN
- 0887-4476 (ISSN-L)
- 1098-2396
- OpenAlex
- W2075962139
- Cited by
- 134
- References
- 5
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 9 · 2021: 3 · 2020: 3 · 2019: 9 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 8 · 2014: 5 · 2013: 4 · 2012: 7
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Synapse (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (T32-DA07316, T32DA007316, DA-06278, F31-DA01587, R01DA006278)
- 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
- amphetamine, methylphenidate, extracellular dopamine, synaptic dopamine, striatum, dopamine transporter, attention deficit hyperactivity disorder, microdialysis, positron emission tomography
- MeSH terms
- Amphetamine, Central Nervous System Stimulants, Animals, Brain, Chromatography, High Pressure Liquid, Dopamine, Female, Male, Methylphenidate, Papio, Synapses, Rats, Sprague-Dawley, Microdialysis, Extracellular Fluid, Positron-Emission Tomography, Rats
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