Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors.
BACKGROUND
Methylphenidate (MPH), a psychostimulant drug used to treat attention-deficit/hyperactivity disorder, produces the effects of increasing alertness and improving attention. However, misuse of MPH has been associated with an increased risk of aggression and psychosis. We sought to determine the molecular mechanism underlying the complex actions of MPH.


METHODS
Adolescent (4-week-old) rats were given one injection of MPH at different doses. The impact of MPH on glutamatergic signaling in pyramidal neurons of prefrontal cortex was measured. Behavioral changes induced by MPH were also examined in parallel.


RESULTS
Administration of low-dose (.5 mg/kg) MPH selectively potentiated N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) via adrenergic receptor activation, whereas high-dose (10 mg/kg) MPH suppressed both NMDAR-mediated and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated EPSCs. The dual effects of MPH on EPSCs were associated with bidirectional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated prefrontal cortex-mediated temporal order recognition memory and attention. Animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of synaptosomal-associated protein 25, a key SNARE protein involved in NMDAR exocytosis, blocked the increase of NMDAR-mediated EPSCs by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and temporal order recognition memory via a mechanism dependent on synaptosomal-associated protein 25.


CONCLUSIONS
These results provide a potential mechanism underlying the cognitive-enhancing effects of low-dose MPH as well as the psychosis-inducing effects of high-dose MPH.
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
Jia
J
Cheng
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
Zhe
Z
Xiong
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
Lara J
LJ
Duffney
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
Jing
J
Wei
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Aiyi
A
Liu
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
Sihang
S
Liu
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Guo-Jun
GJ
Chen
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York; Department of Physiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. Electronic address: zhenyan@buffalo.edu.
Zhen
Z
Yan
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001288:Attention / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D001703:Biophysics; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008376:Maprotiline / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects*; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D010455:Peptides; D010879:Piperazines; D012333:RNA, Messenger; D017470:Receptors, Glutamate; C534628:SCH 23390; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D008774:Methylphenidate; D008376:Maprotiline; D015016:Yohimbine; C043425:vanoxerine
AMPA receptors; NMDA receptors; SNAP-25; methylphenidate; prefrontal cortex; stress