On the other hand, escalating or higher doses of MPH induce behavioral sensitization, like locomotor hyperactivity in animals, , which is associated with a robust DA release in the PFC, caudate-putamen, and nucleus accumbens, etc. And in vitro, MPH could enhance excitability of pyramidal PFC neurons by activating α2 receptors located in interneurons. For example, in vivo acutely administered MPH exerts excitatory actions on PFC neurons by indirectly activating α2-adrenoceptors and D1 receptors, –. Importantly, recent electrophysiological studies explored more on the receptor mechanisms for MPH actions. Through strengthening DA/NE transmission in PFC, low to moderate doses of MPH have been shown to improve working memory in animals. Thus, these evidence support the notion that PFC is a main site involving in MPH’s therapeutic actions. Interestingly, a recent animal study showed that low dose of MPH infusion into PFC facilitates working memory performance, while MPH into striatum does not affect this PFC-dependent cognition task.

As a blocker of dopamine (DA) and norepinephrine (NE) transporters, , low to moderate levels of MPH increase both extracellular DA and NE in PFC, and DA in the striatum. In the ADHD patients, the symptoms are mostly consistent with the dysfunction of the PFC, , where is a high-function area guiding and organizing attention, thought and affection. However, these young people using prescribed MPH improperly for pleasurable enhancement, have high risk of being addicted.

As acutely administered MPH has a good safety profile, and improves executive function performance in both diagnosed ADHD patients and general healthy population –, its prescription has been strikingly increased nowadays. Methylphenidate (MPH, known as Ritalin or Concerta), is a commonly used stimulant medication for Attention-deficit/hyperactivity disorder (ADHD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by grants from the Ministry of Science and Technology of China (2006CB500807 2011CBA00406) and the National Natural Science Foundation of China (30700218, 3082100263). Received: SeptemAccepted: NovemPublished: December 20, 2012Ĭopyright: © 2012 Zhang et al. University of Medicine & Dentistry of NJ - New Jersey Medical School, United States of America (2012) Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.Ĭitation: Zhang C-L, Feng Z-J, Liu Y, Ji X-H, Peng J-Y, Zhang X-H, et al. 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. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. 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. 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.

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). As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD).

Methylphenidate sigma bonds