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      Atomoxetine/Methylphenidate Effects on Social Play Behavior

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          Abstract

          Researchers at Utrecht University, The Netherlands, and University “Roma Tre,” Rome, Italy, studied the neural substrates of the previously identified social play-suppressant effects of methylphenidate (MPH) and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD).

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          Meta-analysis of suicide-related behavior events in patients treated with atomoxetine.

          Mark E Bangs, Sitra Tauscher-Wisniewski, John Polzer … (2008)
          The present work examined suicide-related events in acute, double-blind, and placebo- or active comparator-controlled trials with atomoxetine. Fourteen trials in pediatric patients were included. Potential events were identified in the adverse events database using a text-string search. Potential suicide-related events were categorized according to U.S. Food and Drug Administration-defined codes using blinded patient summaries. The meta-analyses used the Mantel-Haenszel incidence difference and Mantel-Haenszel risk ratio methods. No patient in atomoxetine attention-deficit/hyperactivity disorder (ADHD) trials committed suicide. The frequency of suicidal ideation was 0.37% (5/1357) in pediatric patients taking atomoxetine versus 0% (0/851) for the placebo group; Mantel-Haenszel incidence difference of 0.46 (95% confidence interval 0.09-0.83; p =.016) and Mantel-Haenszel risk ratio of 2.92 (95% confidence interval 0.63-13.57; p =.172). Frequencies of suicide-related events in pediatric patients with ADHD did not differ between methylphenidate and atomoxetine treatments (Mantel-Haenszel incidence difference of -0.12 (95% confidence interval -0.62 to 0.38; p =.649). The number needed to harm in pediatric patients for an additional suicide-related event is 227 compared to the number needed to treat of five to achieve remission of ADHD symptoms. Although uncommon, suicidal ideation was significantly more frequent in pediatric ADHD patients treated with atomoxetine compared to those treated with placebo. Retrospective analysis has limitations in ascertaining intent.
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            Methylphenidate disrupts social play behavior in adolescent rats.

            Louk J. M. J. Vanderschuren, Viviana Trezza, Sanne Griffioen-Roose … (2008)
            Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an alpha-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of alpha-1 adrenoceptors, beta-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate.
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              Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats.

              E. J. Marijke Achterberg, Linda W M van Kerkhof, Ruth Damsteegt … (2015)
              Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pediatr Neurol Briefs
                Journal ID (iso-abbrev): Pediatr Neurol Briefs
                Journal ID (issn): 1043-3155
                Journal ID (pmc): pedneurbriefs
                Journal ID (publisher-id): Pediatr Neurol Briefs
                Title: Pediatric Neurology Briefs
                Publisher: Pediatric Neurology Briefs Publishers (Chicago, IL, USA )
                ISSN (Print): 2166-6482
                ISSN (Electronic): 1043-3155
                Publication date (Print, pub): February 2015
                Publication date (Electronic, pub): 25 February 2015
                Volume: 29
                Issue: 2
                Page: 10
                Affiliations
                [1 ]Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
                [2 ]Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL
                Author notes
                [* ]Correspondence: Dr. J. Gordon Millichap, E-mail: jgmillichap@ 123456northwestern.edu
                Author information
                http://orcid.org/0000-0002-0173-7931
                Article
                Publisher ID: PNB-29-10
                DOI: 10.15844/pedneurbriefs-29-2-1
                PMC ID: 4747285
                PubMed ID: 26933553
                SO-VID: c8b2308e-231e-4bf9-ae09-ba1c00ceda04
                Copyright © Copyright: © 2015 The Author(s)
                License:

                This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 04 February 2015
                Date accepted : 20 February 2015
                Related
                Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats
                Categories
                Subject: Attention Deficit Disorders
                Subject: Neurology
                Subject: Pediatrics
                Subject: Nervous System Diseases
                Subject: Child Development
                Subject: Brain Diseases
                Subject: Neurosurgery
                Subject: Child
                Subject: Infant

                Keywords: amygdala,habenula,methylphenidate,noradrenaline,prefrontal cortex,social play behavior
                Data availability:
                Keywords: amygdala, habenula, methylphenidate, noradrenaline, prefrontal cortex, social play behavior

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