Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex
Abstract
Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in hea…
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Alteration of glutamate/GABA equilibrium has been related to a diminished capability to focus on demanding tasks and to result in DA dysregulation, causing inhibition of defective pyramidal neurons and a decrease shift in excitation towards tasks regulated in the PFC.
“Alteration of glutamate/GABA equilibrium has been related to a diminished capability to focus on demanding tasks [98] and to result in DA dysregulation, causing inhibition of defective pyramidal neurons and a decrease shift in excitation towards tasks regulated in the PFC [99, 100].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [100]
Both psychostimulants and nonstimulants may mitigate the dysfunctional inhibition and execution processing deficits seen in ADHD.
“Through their common neuropsychological actions and partially overlapping pharmacological targets, both psychostimulants and nonstimulants may mitigate the dysfunctional inhibition and execution processing deficits seen in ADHD (Gilbert et al., 2006).”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Gilbert et al., 2006
Psychostimulants and nonstimulants have partially overlapping pharmacological targets.
“Through their common neuropsychological actions and partially overlapping pharmacological targets, both psychostimulants and nonstimulants may mitigate the dysfunctional inhibition and execution processing deficits seen in ADHD (Gilbert et al., 2006).”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Gilbert et al., 2006
Both stimulant and nonstimulant medications used for ADHD have been shown to decrease cortical inhibition and increase cortical facilitation in the SMA.
“Both stimulant and nonstimulant medications used for ADHD have been shown to decrease cortical inhibition and increase cortical facilitation in the SMA”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Gilbert et al., 2006
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“However, the MPH effects on these signalling pathways were totally inhibited using ADRD1B blockers, showing that ADRD1B mediates the phosphorylation of PKA signalling through MPH in the PFC [143].”
BackgroundInfluentialPan, N., Ma, T., Liu, Y., Zhang, S., Hu, S., Shekara, A., Cao, H., Gong, Q., & Chen, Y. (2024) · Psychological Medicine · doi:10.1017/s003329172400285x · Cited by 7 · see citing works
“Both stimulant and nonstimulant medications used for ADHD have been shown to decrease cortical inhibition and increase cortical facilitation in the SMA (Gilbert et al., 2006).”
- Authors
- Gilbert, D. L., Ridel, K. R., Sallee, F. R., Zhang, J., Lipps, T. D., & Wassermann, E. M.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of Cincinnati (US)
- National Institute of Neurological Disorders and Stroke (US)
- Corresponding author
- Gilbert, Donald L
- Venue
- Neuropsychopharmacology
- Published
- 2005-07-20
- Volume
- 31
- Issue
- 2
- Pages
- 442-449
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2019205381
- Cited by
- 97
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 9 · 2013: 8 · 2012: 9
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- American Academy of Neurology
- National Institute of Neurological Disorders and Stroke (K23NS041920, K23 NS41920)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- attention deficit hyperactivity disorder, methylphenidate, atomoxetine, stimulant medication, norepinephrine reuptake inhibitors, motor cortex, cortical inhibition, cortical facilitation, motor evoked potentials, interstimulus interval, transcranial magnetic stimulation
- MeSH terms
- Atomoxetine Hydrochloride, Adult, Attention Deficit Disorder with Hyperactivity, Double-Blind Method, Female, Humans, Male, Methylphenidate, Motor Cortex, Neural Inhibition, Propylamines, Time Factors, Meta-Analysis as Topic, Cross-Over Studies, Adrenergic Uptake Inhibitors, Evoked Potentials, Motor, Transcranial Magnetic Stimulation
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