A lack of functional NK1 receptors explains most, but not all, abnormal behaviours of NK1R‐/‐ mice¹

Abstract

Mice lacking functional neurokinin-1 receptors (NK1R-/-) display abnormal behaviours seen in Attention Deficit Hyperactivity Disorder (hyperactivity, impulsivity and inattentiveness). These abnormalities were evident when comparing the behaviour of separate (inbred: ‘Hom’) wildtype and NK1R-/- mouse strains. Here, we investigated whether the inbreeding protocol could influence their phenotype by comparing the behaviour of these mice with that of wildtype (NK1R+/+) and NK1R-/- progeny of heterozygous parents (‘Het’, derived from the same inbred strains). First, we recorded the spontaneous motor activity of the two colonies/genotypes, over 7 days. This continuous monitoring also enabled us to investigate whether the diurnal rhythm in motor activity differs in the two colonies/genotypes. NK1R-/- mice from both colonies were hyperactive compared with their wildtypes and their diurnal rhythm was also disrupted. Next, we evaluated the performance of the four groups of mice in the 5-Choice Serial Reaction-Time Task (5-CSRTT). During training, NK1R-/- mice from both colonies expressed more impulsive and perseverative behaviour than their wildtypes. During testing, only NK1R-/- mice from the Hom colony were more impulsive than their wildtypes, but NK1R-/- mice from both colonies were more perseverative. There were no colony differences in inattentiveness. Moreover, a genotype difference in this measure depended on time of day. We conclude that the hyperactivity, perseveration and, possibly, inattentiveness of NK1R-/- mice is a direct consequence of a lack of functional NK1R. However, the greater impulsivity of NK1R-/- mice depended on an interaction between a functional deficit of NK1R and other (possibly environmental and/or epigenetic) factors.

Perseveration by NK1R-/- (‘knockout’) mice is blunted by doses of methylphenidate that affect neither other aspects of their cognitive performance nor the behaviour of wild-type mice in the 5-Choice Continuous Performance Test

“…The only behaviour to show a marked genotype difference in NI-2 was perseveration, an abnormality that is also prominent in both NI-1 of this test (Porter et al, 2016) and the 5CSRTT (Dudley et al, 2013; Weir et al, 2014; Yan et al, 2011; Porter et al, 2015a; but see Porter et al, 2015b). Evidently, a deficit in functional NK1R can exacerbate this behaviour.…”

“…This proposition is based on our evidence that male NK1R-/- mice express locomotor hyperactivity compared with their wild types (Fisher et al, 2007; Herpfer et al, 2005; Porter et al, 2015a, 2015b), which is diminished by treatment with d -amphetamine or methylphenidate (Yan et al, 2009). These mutant mice also display impaired cognitive performance and response control in the 5-Choice Serial Reaction Time Task (5CSRTT).…”

The NK1R-/- mouse phenotype suggests that small body size, with a sex- and diet-dependent excess in body mass and fat, are physical biomarkers for a human endophenotype with vulnerability to attention deficit hyperactivity disorder

“…Nevertheless, it would be interesting to carry out a head-to-head comparison of the effect of diet on the performance of the two genotypes in the 5-CRSTT to test the possibility that a high-fat diet aggravates ADHD, as has been suggested for humans (Howard et al 2011), for which there is some preclinical supporting evidence (Marwitz et al, 2015). A further interesting caveat is that circadian rhythms are disrupted in these mice (Porter et al, 2015b) and that disruption of circadian rhythms can increase vulnerability to both obesity and ADHD (Vogel et al, 2015). …”

“…We studied inbred homozygous mice because these mice express all the diagnostic abnormalities seen in ADHD (locomotor hyperactivity, impulsive behaviour, inattentiveness and perseveration). Hyperactivity, inattentiveness and perseveration are also evident in the homozygous (F2) offspring of heterozygote (F1) parents, but their impulsive behaviour arises from an interaction between a lack of functional NK1R and an, as yet unidentified, factor in the breeding environment (Porter et al, 2015b). …”

“…First, comparisons of the locomotor behaviour of NK1R-/- mice and their wildtypes have revealed that the former genotype typically displays locomotor hyperactivity in a range of different experimental settings (Fisher et al, 2007; Herpfer et al, 2005; Moyes et al, 2016; Porter et al, 2015a, 2015b). …”