Behavioural and pharmacological magnetic resonance imaging assessment of the effects of methylphenidate in a potential new rat model of attention deficit hyperactivity disorder.
BACKGROUND
The psychomotor stimulant methylphenidate is used in the treatment of attention deficit hyperactivity disorder (ADHD). Whereas the mechanism is not fully understood it is suggested to involve restoration of impaired dopamine function found in ADHD.


OBJECTIVE
The aim of this study was to determine the effects of methylphenidate on brain region activation in vivo using pharmacological magnetic resonance imaging (phMRI) in a potential rat model of ADHD.


METHODS
Rats were treated bi-daily [from postnatal day (PND) 24] for 4 days with the dopamine re-uptake inhibitor GBR 12909 (30 mg/kg i.p) or vehicle (control). On PND 57 rats were administered methylphenidate (4 mg/kg i.p) and locomotor activity measured. In a separate group of animals, blood oxygen level dependent (BOLD) response was measured using phMRI to determine changes in brain region activation produced by methylphenidate (4 mg/kg i.p.) in GBR 12909-pretreated or control rats.


RESULTS
Methylphenidate produced a greater locomotor-stimulant response in controls compared with GBR 12909 rats. Pretreatment with GBR 12909 reduced the BOLD response produced by methylphenidate compared with that in control animals. The main effects of methylphenidate on the BOLD response were seen in the caudate, frontal cortex, hippocampus and hypothalamus.


CONCLUSIONS
Short-term treatment with GBR 12909 in young rats causes long-term changes in dopaminergic systems, altering the methylphenidate-induced behavioural response and brain region activation compared with that in vehicle-pretreated rats. The results further support the view that altered dopaminergic function may be an important factor in ADHD and the value of animal models with this functional neurochemical deficit.
Hewitt
Katherine N
KN
Institute of Neuroscience, School of Biomedical Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, UK. Katie.hewitt@nottingham.ac.uk
Shah
Yasmene B
YB
Prior
Malcolm J W
MJ
Morris
Peter G
PG
Hollis
Chris P
CP
Fone
Kevin C F
KC
Marsden
Charles A
CA
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D001931:Brain Mapping; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology* / Q000627:therapeutic use; D010100:Oxygen / Q000097:blood; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D008774:Methylphenidate; C043425:vanoxerine; D010100:Oxygen