Oral Administration of Methylphenidate (Ritalin) Affects Dopamine Release Differentially Between the Prefrontal Cortex and Striatum: A Microdialysis Study in the Monkey.
Methylphenidate (MPH; trade name Ritalin) is a widely used drug for the treatment of attention deficit hyperactivity disorder (ADHD) and is often used as a cognitive enhancer. Because MPH increases dopamine (DA) release by blocking the DA transporter in the human striatum, MPH is supposed to work on attention and cognition through a DA increase in the striatum. However, ADHD patients show impaired prefrontal cortex (PFC) function and MPH administration is associated with increased neural activity in the PFC. Although MPH is indicated to increase DA release in the rat PFC, there has been no study to examine MPH-induced DA changes in the human PFC because of technical difficulties associated with the low level of PFC DA receptors. Using the microdialysis technique, we examined the effects of oral administration of MPH on DA release in both the PFC and striatum in the monkey. We also tested the effect of MPH on cognitive task performance. As in human studies, in the striatum, both high and low doses of MPH induced consistent increases in DA release ∼30 min after their administrations. In the PFC, a consistent increase in DA release was observed 1 h after a high dose, but not low doses, of MPH. Low doses of MPH improved cognitive task performance, but a high dose of MPH made the monkey drowsy. Therefore, low-dose MPH-induced cognitive enhancement is supported by striatum DA increase.SIGNIFICANCE STATEMENTMethylphenidate (MPH) is a widely used drug for the treatment of attention deficit hyperactivity disorder and is often used as a cognitive enhancer. Although human positron emission tomography studies suggest that MPH works on attention and cognition through dopamine (DA) changes in the striatum, there has been no study to examine MPH-induced DA changes in the human prefrontal cortex (PFC). Using the microdialysis technique in monkeys, we found, for the first time, that low doses of MPH consistently increased DA release in the striatum but did not in the PFC. Cognitive enhancement effects of low doses of MPH are supposed to be supported by the striatum DA increase.
Department of Physiological Psychology, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and.
Tohru
T
Kodama
Department of Physiological Psychology, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and.
Takashi
T
Kojima
Department of Physiological Psychology, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and.
Yoshiko
Y
Honda
Department of Physiological Psychology, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and.|Division of Systems Neuroscience, Tohoku University Graduate School of Life Sciences, Aoba-ku, Sendai 980-8577, Japan.
Takayuki
0000-0002-2511-4341
T
Hosokawa
Division of Systems Neuroscience, Tohoku University Graduate School of Life Sciences, Aoba-ku, Sendai 980-8577, Japan.
Ken-Ichiro
0000-0001-5781-2948
KI
Tsutsui
Department of Physiological Psychology, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and watanabe-ms@igakuken.or.jp.
Masataka
0000-0001-8281-2675
M
Watanabe
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007266:Inhibition, Psychological; D008253:Macaca mulatta; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D017551:Microdialysis; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000187:drug effects*; D011930:Reaction Time / Q000187:drug effects; D012649:Self Concept; D013997:Time Factors
D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D004298:Dopamine
dopamine; methylphenidate; microdialysis; monkey; prefrontal cortex; striatum