Abstract
BackgroundThe 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 ResultsThe 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.ConclusionIn 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.
Highlights
Attention Deficit Hyperactivity Disorder (ADHD) is a heritable, developmental disorder that affects between 2–5% of children in the UK but is prevalent worldwide [1]
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
The incidence of premature responses across Stages 1–6 was greater in wildtype mice than NK1R-/- mice, overall (F(1,43) = 11.5, P,0.001) (Fig. 1F) and increased transiently in both genotypes during Stage 3 of training, as has been reported previously [19]
Summary
Attention Deficit Hyperactivity Disorder (ADHD) is a heritable, developmental disorder that affects between 2–5% of children in the UK but is prevalent worldwide [1]. Three compounds are licensed to treat ADHD in the UK (d-amphetamine, methylphenidate and atomoxetine) [4] but guanfacine and the prodrug, lisdexamfetamine, are available in the USA [5]. All these compounds augment monoamine transmission in the brain and periphery. Their predictable hemodynamic side-effects, the unease about long-term use of the psychostimulants, d-amphetamine and methylphenidate (especially in children), and their lack of efficacy in approximately 20–25% of patients (e.g., [6]), justify the need for a better understanding of the neurobiological abnormalities underlying ADHD and development of alternative drug treatments. Prompted by evidence that circadian rhythms are disrupted in ADHD, we compared the performance of mice that were trained and tested in the morning or afternoon
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