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

Abstract

The underlying cause(s) of abnormalities expressed by patients with attention deficit hyperactivity disorder (ADHD) have yet to be delineated. One factor that has been associated with increased vulnerability to ADHD is polymorphism(s) of TACR1, which is the human equivalent of the rodent NK1 (substance P-preferring) receptor gene (Nk1r). We have reported previously that genetically altered mice, lacking functional NK1R (NK1R–/–), express locomotor hyperactivity, which was blunted by the first-line treatment for ADHD, methylphenidate. Here, we compared the effects of this psychostimulant (3, 10 and 30 mg/kg, intraperitoneally) on the behaviour of NK1R-/- mice and their wild types in the 5-Choice Continuous Performance Test, which emulates procedures used to study attention and response control in ADHD patients. Methylphenidate increased total trials (a measure of ‘productivity’) completed by wild types, but not by NK1R-/- mice. Conversely, this drug reduced perseveration by NK1R-/- mice, but not by wild types. Other drug-induced changes in key behaviours were not genotype dependent, especially at the highest dose: for example, % omissions (an index of inattentiveness) was increased, whereas % false alarms and % premature responses (measures of impulsivity) declined in both genotypes, indicating reduced overall response. These findings are discussed in the context of the efficacy of methylphenidate in the treatment of ADHD. Moreover, they lead to several testable proposals. First, methylphenidate does not improve attention in a subgroup of ADHD patients with a functional deficit of TACR1. Second, these patients do not express excessive false alarms when compared with other groups of subjects, but they do express excessive perseveration, which would be ameliorated by methylphenidate.

A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD‐associated cognitive phenotypes

“…The 30 min interval is sufficient to produce elevation of plasma and brain MPH as well as brain dopamine content in rodent models (Kuczenski and Segal, 2005, 2001; Wargin et al, 1983; Patrick et al, 1984; Thai et al, 1999; Kotaki et al, 1988; Berridge et al, 2006). Moreover, intraperitoneal MPH produces significant effects on attention and working memory in rodents within 30 min (Pillidge et al, 2016; Berridge et al, 2006).…”

“…A number of animal models of ADHD have been described and used in preclinical research (Sagvolden et al, 2005(Sagvolden et al, , 1992Sagvolden and Johansen, 2012;Russell, 2007;Yan et al, 2011Yan et al, , 2009Pillidge et al, 2016;Porter et al, 2016). The majority are rodent models, and the most commonly analyzed behavioral phenotypes are hyperactivity and attention deficit.…”

Methylphenidate Dose-Dependently Affects Aggression and Improves Fear Extinction and Anxiety in BALB/cJ Mice

“…Injection sides were alternated in order to reduce tissue damage. The dosage of MPH administered to the mice was based on previous animal studies that have investigated locomotor activity and cognition in rodents (in details explained by 31). The dose of 3 mg/kg resembles the therapeutic window of treatment of ADHD in humans, while the 10 mg/kg dose may reflect more the recreational use of MPH (32, 33).…”

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

“…By contrast, NK1R-/- mice did not express excessive ‘false alarms’ (another index of impulsive behaviour (response inhibition)) in the 5-Choice Continuous Performance Test (5C-CPT; Porter et al, 2016). However, these mice performed excessive perseverative responses in both the 5CSRTT and the 5C-CPT (Pillidge et al, 2016; Yan et al, 2011): this behaviour is thought to reflect the repeated cognitive ‘checking’ behaviour expressed by ADHD patients (Gürkan et al, 2015). …”

“…Thirdly, one, or more, of these behavioural abnormalities of NK1R-/- mice is ameliorated by all four compounds that are licensed for treatment of ADHD: guanfacine (inattentiveness: Pillidge et al, 2014a); atomoxetine (impulsivity (premature responses): Pillidge et al, 2014b); d -amphetamine and methylphenidate (locomotor hyperactivity and perseveration: Pillidge et al, 2016; Yan et al, 2009, 2011). …”