The behavioural response of mice lacking NK₁ receptors to guanfacine resembles its clinical profile in treatment of ADHD

Abstract

BACKGROUND AND PURPOSEMice with functional ablation of substance P-preferring neurokinin-1 receptors (NK1R−/− mice) display behavioural abnormalities resembling those in attention deficit hyperactivity disorder (ADHD). Here, we investigated whether the ADHD treatment, guanfacine, alleviated the hyperactivity and impulsivity/inattention displayed by NK1R−/− mice in the light/dark exploration box (LDEB) and 5-choice serial reaction–time task (5-CSRTT), respectively. Following reports of co-morbid anxiety in ADHD, we also investigated effects of guanfacine on anxiety-like behaviour displayed by NK1R−/− and wild-type (WT) mice in the elevated plus maze (EPM).EXPERIMENTAL APPROACHMice were treated with guanfacine (0.1, 0.3 or 1.0 mg·kg−1, i.p.), vehicle or no injection and tested in the 5-CSRTT or the LDEB. Only the lowest dose of guanfacine was used in the EPM assays.KEY RESULTSIn the 5-CSRTT, a low dose of guanfacine (0.1 mg·kg−1) increased attention in NK1R−/− mice, but not in WT mice. This dose did not affect the total number of trials completed, latencies to respond or locomotor activity in the LDEB. Impulsivity was decreased by the high dose (1.0 mg·kg−1) of guanfacine, but this was evident in both genotypes and is likely to be secondary to a generalized blunting of behaviour. Although the NK1R−/− mice displayed marked anxiety-like behaviour, guanfacine did not affect the behaviour of either genotype in the EPM.CONCLUSIONS AND IMPLICATIONSThis evidence that guanfacine improves attention at a dose that did not affect arousal or emotionality supports our proposal that NK1R−/− mice express an attention deficit resembling that of ADHD patients.LINKED ARTICLESThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20

Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor ‘knockout’ mice

“…Rodent chow was obtained from Harlan UK (2018 global Rodent Diet). All the mice derived from inbred homozygous strains (see: Yan et al, 2010; Pillidge et al, 2014 ) and were of a 129/Sv × C57BL/6J background, backcrossed with an outbred MF1 strain many generations ago ( de Felipe et al, 1998 ).…”

“…The ADHD treatments, amphetamine, methylphenidate and guanfacine, all reduce the hyperactivity of these mice ( Pillidge et al, 2014; Yan et al, 2010 ). Although amphetamine did not reduce the impulsivity/inattention displayed by NK1R −/− mice in the 5-CSRTT, the non-stimulant guanfacine, did ( Pillidge et al, 2014; Yan et al, 2011 ).…”

“…The ADHD treatments, amphetamine, methylphenidate and guanfacine, all reduce the hyperactivity of these mice ( Pillidge et al, 2014; Yan et al, 2010 ). Although amphetamine did not reduce the impulsivity/inattention displayed by NK1R −/− mice in the 5-CSRTT, the non-stimulant guanfacine, did ( Pillidge et al, 2014; Yan et al, 2011 ). The proposal that these mice could be used to study the aetiology of ADHD-like behaviours in vivo is supported by evidence that TACR1 (the human equivalent of the NK1R gene) polymorphisms are associated with ADHD ( Sharp et al, 2009, 2014; Yan et al, 2010 ).…”

The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs

“…Consistent with these results, the a 2 -adrenergic receptor agonist guanfacine [N-(diaminomethylidene)-2-(2,6-dichlorophenyl) acetamide] suppressed, while the a 2 -adrenergic receptor antagonist yohimbine (methyl (1S,15R,18S,19R,20S)-18-hydroxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate) increased, 5-CSRTT premature responses in rats (Sun et al, 2010;Fernando et al, 2012;Pillidge et al, 2014). Thus, while more work remains to clarify the role of specific a 1 -and a 2 -adrenergic subtypes on 5-CSRTT and DRL 72-second behavior, converging pharmacological evidence for NET inhibitors and b 2 -, a 1 -, and a 2 -adrenergic receptor agonists supports the hypothesis that motoric impulsivity is an important aspect for both behavioral paradigms.…”

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

“…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). …”