ArticlePloS one2012
Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Chronic Combined Oral Methylphenidate and Fluoxetine Increases Inflammation in Somatosensory and Mesolimbic Brain Regions.Neurochemical research · 2025Article
- Ameliorative Effects of High-Intensity Interval Training (HIIT) and Methylphenidate Against Tramadol-Induced Cognitive Impairment: The Role of Hippocampal Oxidative Stress.Brain and behavior · 2025Article
- Review
- Central Med23 deficiency leads to malformation of dentate gyrus and ADHD-like behaviors in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Unraveling Attention-Deficit/Hyperactivity Disorder Etiology: Current Challenges and Future Directions in Treatment.NeuroSci · 2025Review
- Glutamate receptor genetic variants affected peripheral glutamatergic transmission and treatment induced improvement of Indian ADHD probands.Scientific reports · 2023Article
- Molecular Mechanisms Underlying NMDARs Dysfunction and Their Role in ADHD Pathogenesis.International journal of molecular sciences · 2023Review
- Article
- Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review.Neurology and therapy · 2022Review
- The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment.Frontiers in neuroscience · 2022Review
- Methods to Develop anFrontiers in psychiatry · 2021Article
- Microglial P2Y12 receptor regulates ventral hippocampal CA1 neuronal excitability and innate fear in mice.Molecular brain · 2019Article
- PharmGKB summary: methylphenidate pathway, pharmacokinetics/pharmacodynamics.Pharmacogenetics and genomics · 2019Review
- Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases.Frontiers in neuroscience · 2019Review
- Chronic oral methylphenidate treatment increases microglial activation in rats.Journal of neural transmission (Vienna, Austria : 1996) · 2018Article
- Sigma receptors [σRs]: biology in normal and diseased states.Journal of receptor and signal transduction research · 2016Article
- From Clinical Application to Cognitive Enhancement: The Example of Methylphenidate.Current neuropharmacology · 2016Review
- Methylphenidate Increases Glutamate Uptake in Bergmann Glial Cells.Neurochemical research · 2015Article
- Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors.Psychopharmacology · 2015Article
- Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors.Biological psychiatry · 2014Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+) increase, but does not require PKA and extracellular Ca(2+) influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.