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Background  The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by  d -amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon.    Methods and Results  The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without,  d -amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater  omissions  (inattentiveness),  perseveration  and  premature responses  (impulsivity) in the 5-CSRTT. In NK1R-/- mice,  perseveration  in the LITI was increased by injection-stress but reduced by  d -amphetamine.  Omissions  by NK1R-/- mice in the VITI were unaffected by  d -amphetamine, but  premature responses  were exacerbated by this psychostimulant.  Omissions  in the VITI were higher, overall, in the morning than the afternoon but, in the LITI,  premature responses  of NK1R-/- mice were higher in the afternoon than the morning.    Conclusion  In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because  d -amphetamine reduced  perseveration  in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of  omissions  and  premature responses  in NK1R-/- mice given  d -amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies.

Performance Deficits of NK1 Receptor Knockout Mice in the 5-Choice Serial Reaction-Time Task: Effects of d-Amphetamine, Stress and Time of Day