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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Psychiatry | doi: 10.3389/fpsyt.2019.00768

Methylphenidate dose-dependently affects aggression, and improves fear extinction and anxiety in BALB/cJ mice

 Amanda Jager1, Doranda Kanters1, Femke Geers1,  Jan K. Buitelaar1,  Tamas Kozicz2, 3 and  Jeffrey C. Glennon1*
  • 1Donders Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Netherlands
  • 2Donders Institute for Brain, Cognition and Behaviour, Radboud University, Netherlands
  • 3Center for Individualized Medicine, Mayo Clinic, United States

Overt aggression, increased anxiety and dysfunctional fear processing are often observed in individuals with conduct disorder (CD) and attention-deficit hyperactivity disorder (ADHD). Methylphenidate (MPH), a psychostimulant increasing dopamine and noradrenaline tone, is effective in reducing aggression in both CD and ADHD individuals. However, it is unclear to which extent these effects of MPH are dose-dependent. Here, the effects of acute intraperitoneal MPH (3 and 10 mg/kg) on aggression, anxiety, social behavior and fear extinction were investigated in BALB/cJ mice. Previous studies in BALB/cJ mice have revealed high levels of aggression and anxiety that are associated with reduced top-down cortical control. Administration of 3 mg/kg MPH prolonged the attack latency and prevented escalation of aggression over time compared to vehicle treated mice, while 10 mg/kg MPH increased number of bites and attacks. In addition, 3 mg/kg MPH decreased social interaction slightly. A strong anxiolytic effect was found after administration of both the 3 mg/kg and 10 mg/kg doses in the elevated plus maze and the open field test. In addition, while vehicle-treated BALB/cJ animals showed intact freezing, both doses of MPH decreased freezing to the unconditioned stimulus in a fear-conditioning paradigm. A long-lasting effect on fear extinction was visible after treatment with the 10 mg/kg dose. The data support a role for MPH in the regulation of anxiety, fear processing and aggression in BALB/cJ mice, with the latter effect in a dose-dependent manner. The findings provide a further context for examining the effects of MPH in clinical disorders as ADHD and CD.

Keywords: Aggression, Animal – mouse, Anxiety, Attentiondeficit hyperactivity disorder, Conduct (behavioural) problems, Methylphenidate (MPH)

Received: 03 Jun 2019; Accepted: 24 Sep 2019.

Copyright: © 2019 Jager, Kanters, Geers, Buitelaar, Kozicz and Glennon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jeffrey C. Glennon, Donders Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands,