Effects of long-term methylphenidate treatment in adolescent and adult rats on hippocampal shape, functional connectivity and adult neurogenesis.
Methylphenidate (MPH) is a widely prescribed stimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Its use in this age group raises concerns regarding the potential interference with ongoing neurodevelopmental processes. Particularly the hippocampus is a highly plastic brain region that continues to develop postnatally and is involved in cognition and emotional behavior, functions known to be affected by MPH. In this study, we assessed whether hippocampal structure and function were affected by chronic oral MPH treatment and whether its effects were different in adolescent or adult rats. Using behavioral testing, resting-state functional MRI, post-mortem structural magnetic resonance imaging (MRI), and immunohistochemistry, we assessed MPH's effects on recognition memory, depressive-like behavior, topological features of functional connectivity networks, hippocampal shape and markers for hippocampal neurogenesis and proliferation. Object recognition memory was transiently impaired in adolescent treated rats, while in animals treated during adulthood, increased depressive-like behavior was observed. Neurogenesis was increased in adolescent treated rats, whereas cell proliferation was decreased following adult treatment. Adolescent treated rats showed inward shape deformations adjacent to ventral parahippocampal regions known to be involved in recognition memory, whereas such deformations were not observed in adult treated animals. Irrespective of the age of treatment, MPH affected topological features of ventral hippocampal functional networks. Thus, chronic oral treatment with a therapeutically relevant dose of MPH preferentially affected the ventral part of the hippocampus and induced contrasting effects in adolescent and adult rats. The differences in behavior were paralleled by opposite effects on adult neurogenesis and granule cell proliferation.
Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
K
K
van der Marel
Normandie Univ, UCBN, Groupe Mémoire et Plasticité comportementale (GMPc) EA 4259, UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, France.
V
V
Bouet
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
G F
GF
Meerhoff
Normandie Univ, UCBN, Groupe Mémoire et Plasticité comportementale (GMPc) EA 4259, UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, France.
T
T
Freret
Normandie Univ, UCBN, Groupe Mémoire et Plasticité comportementale (GMPc) EA 4259, UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, France.
M
M
Boulouard
Normandie Univ, UCBN, Groupe Mémoire et Plasticité comportementale (GMPc) EA 4259, UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, France.
F
F
Dauphin
Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
A
A
Klomp
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
P J
PJ
Lucassen
Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
J R
JR
Homberg
Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
R M
RM
Dijkhuizen
Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: L.Reneman@amc.uva.nl.
L
L
Reneman
D000284:Administration, Oral; D000375:Aging / Q000187:drug effects / Q000473:pathology / Q000502:physiology / Q000523:psychology; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003866:Depressive Disorder / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology* / Q000502:physiology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008774:Methylphenidate / Q000633:toxicity*; D009434:Neural Pathways / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D012146:Rest
D000697:Central Nervous System Stimulants; D008774:Methylphenidate
MRI; depressive-like behavior; hippocampus; memory; methylphenidate; neurogenesis