Chronic Methylphenidate Alters Tonic and Phasic Glutamate Signaling in the Frontal Cortex of a Freely-Moving Rat Model of ADHD

Neurochem Res. 2019 Jan;44(1):89-101. doi: 10.1007/s11064-018-2483-1. Epub 2018 Feb 3.


Glutamate dysfunction has been implicated in a number of substance of abuse studies, including cocaine and methamphetamine. Moreover, in attention-deficit/hyperactivity disorder (ADHD), it has been discovered that when the initiation of stimulant treatment occurs during adolescence, there is an increased risk of developing a substance use disorder later in life. The spontaneously hypertensive rat (SHR) serves as a phenotype for ADHD and studies have found increased cocaine self-administration in adult SHRs when treated with the stimulant methylphenidate (MPH) during adolescence. For this reason, we wanted to examine glutamate signaling in the pre-limbic frontal cortex, a region implicated in ADHD and drug addiction, in the SHR and its progenitor control strain, the Wistar Kyoto (WKY). We chronically implanted glutamate-selective microelectrode arrays (MEAs) into 8-week-old animals and treated with MPH (2 mg/kg, s.c.) for 11 days while measuring tonic and phasic extracellular glutamate concentrations. We observed that intermediate treatment with a clinically relevant dose of MPH increased tonic glutamate levels in the SHR but not the WKY compared to vehicle controls. After chronic treatment, both the SHR and WKY exhibited increased tonic glutamate levels; however, only the SHR was found to have decreased amplitudes of phasic glutamate signaling following chronic MPH administration. The findings from this study suggest that the MPH effects on extracellular glutamate levels in the SHR may potentiate the response for drug abuse later in life. Additionally, these data illuminate a pathway for investigating novel therapies for the treatment of ADHD and suggest that possibly targeting the group II metabotropic glutamate receptors may be a useful therapeutic avenue for adolescents diagnosed with ADHD.

Keywords: ADHD; Phasic glutamate; Pre-limbic cortex; Spontaneously hypertensive rat; Tonic glutamate.

MeSH terms

  • Animals
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Attention Deficit Disorder with Hyperactivity / metabolism*
  • Central Nervous System Stimulants / administration & dosage*
  • Central Nervous System Stimulants / toxicity
  • Disease Models, Animal*
  • Drug Administration Schedule
  • Electrodes, Implanted
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism*
  • Glutamic Acid / metabolism*
  • Male
  • Methylphenidate / administration & dosage*
  • Methylphenidate / toxicity
  • Movement / drug effects
  • Movement / physiology
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Species Specificity


  • Central Nervous System Stimulants
  • Methylphenidate
  • Glutamic Acid