The NK1 receptor knockout mouse model of attention deficit hyperactivity disorder: effects of d-Amphetamine on impaired cognitive performance/response control in the 5-choice serial reaction time task

TC Yan1, RK Weir2, JA Dudley2, EM Grabowska1, YP Oliver3, TL Ripley3, SP Hunt2, DN Stephens3, SC Stanford1. 1UCL, Department of Neuroscience, Physiology & Pharmacology, London, WC1E 6BT, United Kingdom, 2UCL, Department of Cell & Developmental Biology, London, WC1E 6BT, United Kingdom, 3University of Sussex, School of Psychology, Brighton, BN1 9RH, United Kingdom.

Behavioural and neurochemical abnormalities in mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble those associated with Attention Deficit Hyperactivity Disorder (ADHD). These include hyperactivity, which is prevented by d-amphetamine (d-AMP), a first-line medication for ADHD (see: Yan et al, 2009). Here, we used the 5-Choice Serial Reaction Time Task (5-CSRTT; Carli et al, 1983) to test whether NK1R-/- mice show impulsivity and inattentiveness, which are further key features in ADHD, and whether any such deficits are corrected by d-AMP.

Male NK1R+/+ and NK1R-/- mice (25-35g, 129/Sv X C57BL/6 crossed with an outbred MF1 strain) were food-deprived to 90% of their free-feeding weights and trained in the 5-CSRTT (Oliver et al, 2009). After animals’ performance had stabilized at the criterion for testing (4-13 weeks), the interval between the start of each trial and the light cue was increased from 5s to 7s (‘LITI’) so as to promote %premature responding (impulsivity) and %omissions (inattentiveness). Then, at weekly intervals, animals were given an i.p. injection of either: (a) saline (10 ml/kg), (b) d-AMP (0.3 mg/kg) or (c) d-AMP (1 mg/kg) 30 min before the LITI test or (d) retested with no injection (in order to distinguish differences in task acquisition/recall from any effect of the injection of saline or drug treatment (N = 12/group). The sequence of these treatments was randomized and each was given only once to every mouse. This protocol was then repeated with a variable inter-trial interval (VITI; ITI = 2, 5, 10 or 15s), which minimizes responding to the signal of time elapsed since the light cue. Differences in animals’ performance in the 5-CSRTT were analyzed by split-plot ANOVA with post hoc parametric or nonparametric tests, as appropriate.

The baseline performance of the two genotypes did not differ, except for a small increase (+17%; t22 = 4.3, P<0.001) in latency to collect the reward in NK1R-/- mice. In the LITI test, the knockouts perseverated more than wildtypes (+135%; t22 = 2.5, P<0.05): aggravation of this behaviour by a saline injection (+48%) was prevented by d-AMP (F2,34 = 5.5, P<0.05). In the VITI test, the genotype differences in perseveration and %omissions were abolished by d-AMP. The mutants also showed slightly lower %accuracy (-3%; F1,23 = 5.5, P<0.05) and increased latency to correct responding (+15%; F1,23 = 7.6, P<0.05) as well as greater %premature responding (+57%; F1,23 = 4.5, P<0.05) than the wildtypes: these differences were not diminished by d-AMP. The findings indicate that deficits in cognitive performance/response control seen in NK1R-/- mice were manifested to different extents in the LITI and VITI tests, as was their modification by d-AMP. These results support our proposals that NK1R-/- mice are a model of ADHD and that certain symptoms of this disorder are a consequence of impaired NK1 receptor function.

Carli M et al, 1983. Behavioural Brain Research, 9: 361-380.

Yan TC et al, 2009. Neuropharmacology, 57: 627-635.

Oliver YP et al, 2009. Psychopharmacology, 204: 679-692.

This work was funded by the Medical Research Council (UK).