The influence of test experience and NK1 receptor antagonists on the performance of NK1R-/- and wild type mice in the 5-Choice Serial Reaction-Time Task

Abstract

Genetically-altered mice, lacking functional NK1 receptors (NK1R-/-), express abnormal behaviours that are prominent in Attention Deficit Hyperactivity Disorder: namely, inattentiveness and impulsivity (indicated by their greater % omissions and premature responses in the 5-Choice Serial ReactionTime Task (5-CSRTT) and locomotor hyperactivity. We investigated how behaviour in the 5-CSRTT is affected by repeated testing and whether the abnormalities expressed by NK1R-/-mice are mimicked by treating wild type mice with a NK1R antagonist (L 733060 or RP 67580; 5 or 10 mg/kg). Repeated testing with a variable (VITI) or fixed, prolonged (LITI) intertrial interval reduced % omissions. Premature responses also declined, but only in NK1R-/-mice, in the VITI test. By contrast, perseveration increased in both genotypes. RP 67580 (10 mg/kg) increased the % omissions in both genotypes in the VITI, an action which cannot be attributed to NK1R antagonism. Neither drug affected perseveration. However, for premature responses, the response profile suggested that the low and high doses of RP 67580 (VITI) and L 733060 (LITI) had opposing effects on this behaviour. We infer that the effect of NK1R antagonists in the 5-CSRTT is confounded by animals' test experience and non-specific drug effects at sites other than NK1R, possibly L-type Ca 2+ v channels.

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

“…Our previous experiments have confirmed that repeated experience of the VITI can influence behaviour in this test (see Weir et al ., 2014 ). For this reason, the response to guanfacine in this study was compared with NI-2, which was the uninjected control embedded within the series of drug treatments.…”

“…These drug doses were chosen because they modify relevant aspects of behaviour in mice: for example, working memory in a T-maze (Franowicz et al ., 2002 ) and locomotor activity (Archer and Fredriksson, 2003 ). NI-2 (baseline behaviour of uninjected mice) was embedded within the sequence of vehicle/drug treatments to control for any systematic changes in behaviour arising from rehearsal of the test (see Weir et al ., 2014 ). The vehicle/drug/NI-2 sessions were counterbalanced across subjects, using a pseudo William’s Latin square, such that each mouse received each treatment, or NI-2 session, once only.…”

“…AM session/PM session). Our previous studies indicated that time of testing influences behaviour in the 5-CSRTT (Yan et al ., 2011 ; Weir et al ., 2014 ) and so this was used as a blocking factor, to account for any additional variance in the data. This factor was collapsed across all subjects if there was no effect of time of day on a given dependent variable.…”

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

“…We have not carried out a randomised, head-to-head comparison of the two genotypes in the 5CSRTT and 5C-CPT. However, our findings so far suggest that the longer LITI, used in the 5CSRTT, is more effective than the protocol in this 5C-CPT for discerning a higher proportion of omission errors in NK1R–/– mice than in wild types (Porter et al, 2015a; Weir et al, 2014; Yan et al, 2011; see also Porter et al, 2016). …”

“…These mutant mice also display impaired cognitive performance and response control in the 5-Choice Serial Reaction Time Task (5CSRTT). Typically, they score more % premature responses (an index of impulsivity) and % omissions (an index of inattentiveness) than wild types (Dudley et al, 2013; Porter 2015a, 2015b; Yan et al, 2011), especially when tested for the first time (Weir et al, 2014). It is striking that these three behavioural abnormalities meet the diagnostic criteria for ADHD in humans.…”