title: Long-term oral methylphenidate treatment in adolescent and adult rats: differential effects on brain morphology and function.
abstract: Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral methylphenidate (5 mg/kg) vs vehicle treatment on brain structure and function in adolescent (post-natal day [P]25) and adult (P65) rats. Following a 1-week washout period, we used multimodal magnetic resonance imaging (MRI) to assess effects of age and treatment on independent component analysis-based functional connectivity (resting-state functional MRI), D-amphetamine-induced neural activation responses (pharmacological MRI), gray and white matter tissue volumes and cortical thickness (postmortem structural MRI), and white matter structural integrity (postmortem diffusion tensor imaging (DTI)). Many age-related differences were found, including cortical thinning, white matter development, larger dopamine-mediated activation responses and increased striatal functional connectivity. Methylphenidate reduced anterior cingulate cortical network strength in both adolescents and adults. In contrast to clinical observations from ADHD patient studies, methylphenidate did not increase white matter tissue volume or cortical thickness in rat. Nevertheless, DTI-based fractional anisotropy was higher in the anterior part of the corpus callosum following adolescent treatment. Furthermore, methylphenidate differentially affected adolescents and adults as evidenced by reduced striatal volume and myelination upon adolescent treatment, although we did not observe adverse treatment effects on striatal functional activity. Our findings of small but significant age-dependent effects of psychostimulant treatment in the striatum of healthy rats highlights the importance of further research in children and adolescents that are exposed to methylphenidate.
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kajo
authors.initials: K
authors.lastname: van der Marel
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: Klomp
authors.affiliation: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gideon F
authors.initials: GF
authors.lastname: Meerhoff
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Schipper
authors.affiliation: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lucassen
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Homberg
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Dijkhuizen
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Reneman
mesh_terms: D000284:Administration, Oral; D000375:Aging / Q000473:pathology* / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate