title: Behavioural characterisation of the effects of acute and repeated administration of GBR 12909 in rats: further evaluation of a potential model of ADHD.
abstract: Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterised by excessive levels of hyperactivity, inattentiveness and impulsivity. Stimulant drugs which increase dopamine neurotransmission are treatments for ADHD. Hypodopaminergic fronto-striatal function with associated overactivity of the dopamine transporter (DAT) represents one possible neurobiological mechanism underlying ADHD. Few, if any, of the existing animal models of ADHD mimic the underlying neurobiology of the disorder. In this study we have further characterised the behavioural profile of a model of a hyperactive inattentive animal through manipulation of the DAT. The behavioural effects of acute treatment and following withdrawal from sub-chronic treatment with GBR 12909 (30 mg/kg i.p.), a potent and highly selective DAT inhibitor, were examined in juvenile rats. GBR 12909 treatment was used to produce a compensatory up regulation following withdrawal. Acute treatment with GBR 12909 (30 mg/kg i.p.) resulted in a marked increase in locomotor and rearing behaviours on the first and fourth days during a 4 consecutive bi-daily drug treatment regime in postnatal weaned rats. Adolescent rats after 10, 20 and 30 days withdrawal from GBR 12909 pre-treatment maintained mild increases in locomotor activity and failed to discriminate a familiar over a novel object in the novel object discrimination task (using both 1 min and 3 h inter-trial intervals) indicating impaired learning and memory. Prepulse inhibition of acoustic startle was unaltered following withdrawal from GBR 12909 treatment. These data reinforce the potential role of the DAT in the underlying neurobiology of ADHD. They also add further evidence to suggest that postnatal changes in the DAT following withdrawal from treatment with the DAT inhibitor, GBR 12909, may prove to be a useful animal model of ADHD with potential for examining the effectiveness of novel ADHD treatments.
authors.affiliation: Institute of Neuroscience, School of Biomedical Sciences, Medical School, Queens Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. katie.hewitt@nottingham.ac.uk
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Hewitt
authors.forename: Charles A
authors.initials: CA
authors.lastname: Marsden
authors.forename: Chris P
authors.initials: CP
authors.lastname: Hollis
authors.forename: Kevin C F
authors.initials: KC
authors.lastname: Fone
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects
chemical_list: D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine