title: Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats.
abstract: 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.
authors.affiliation: Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors.forename: E J Marijke
authors.initials: EJ
authors.lastname: Achterberg
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands, and.
authors.forename: Linda W M
authors.initials: LW
authors.lastname: van Kerkhof
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands, and.
authors.forename: Ruth
authors.initials: R
authors.lastname: Damsteegt
authors.affiliation: Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre," 00146 Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Trezza
authors.affiliation: Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands, Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands, and l.j.m.j.vanderschuren@uu.nl.
authors.forename: Louk J M J
authors.initials: LJ
authors.lastname: Vanderschuren
mesh_terms: D000818:Animals; D000069445:Atomoxetine Hydrochloride; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular; D007398:Interpersonal Relations; D008032:Limbic System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage*; D010988:Play and Playthings; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011437:Propylamines / Q000008:administration & dosage*; D051381:Rats
chemical_list: D000697:Central Nervous System Stimulants; D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride
keywords: amygdala; habenula; methylphenidate; noradrenaline; prefrontal cortex; social play behavior