Disruption of noradrenergic transmission and the behavioural response to a novel environment in NK1R–/– mice

Abstract

The behaviour of neurokinin-1-receptor gene knockout (NK1R-/-) mice, which lack functional, substance P-preferring receptors, resembles that of NK1R+/+ mice treated with an antidepressant. Because all antidepressants increase central monoamine transmission, we have investigated whether noradrenergic transmission is increased in NK1R-/- mice and, if so, whether this could influence their behaviour. In anaesthetized subjects, the concentration of extracellular noradrenaline in NK1R-/- mice was two-fourfold greater than in NK1R+/+ mice. Systemic administration of the alpha2-adrenoceptor antagonist, 2-(2,3-dihydro-2-methoxy-1,4-benzodioxan-2-yl)-4,5-dihydro-1H-imidazoline (RX 821002), in anaesthetized or freely moving animals increased extracellular noradrenaline in NK1R+/+ mice only. This suggests that the function of alpha2a-autoreceptors, which modulate noradrenergic transmission, is impaired in NK1R-/- mice. Consistent with this, [35S]GTPgammaS binding to activated alpha2a-adrenoceptors was lower (-70%) in the locus coeruleus, but not the frontal cortex, of NK1R-/- mice compared with their NK1R+/+ counterparts. RX 821002-pretreatment, followed by retrodialysis of the noradrenaline reuptake inhibitor, desipramine, into the frontal cortex of anaesthetized mice increased extracellular noradrenaline to the same extent in the two genotypes. Western blots confirmed that there was no difference in the amount of noradrenaline transporter protein in NK1R-/- and NK1R+/+ mice. Finally, the effects of RX 821002 on certain behaviours in a light/dark exploration box were blunted in NK1R-/- mice, but there was no consistent effect on anxiety-like behaviour in the two genotypes. It is concluded that the greater basal efflux of noradrenaline in NK1R-/- mice is explained by increased transmitter release, coupled with desensitization of somatodendritic alpha2a-adrenoceptors. These changes could contribute to the difference in the behavioural phenotypes.

Antagonism of L-type Cav channels with nifedipine differentially affects performance of wildtype and NK1R−/− mice in the 5-Choice Serial Reaction-Time Task

“…Another potential confounder is that nifedipine can induce lethargy but we believe this is unlikely to have arisen here because the total locomotor activity of the two genotypes did not differ in the light/dark box after drug treatment (c.f., hyperactivity of untreated NK1RÀ/À and wildtype mice in the novel, light zone of the apparatus: Herpfer et al, 2005;Fisher et al, 2007;Yan et al, 2009). Similarly, locomotor activity of wildtype and Cav1.3À/À mice does not differ in an open field (Busquet et al, 2010).…”

“…Specifically, evidence from microdialysis studies indicates that release of serotonin (Froger et al, 2001) and noradrenaline (Herpfer et al, 2005;Fisher et al, 2007) are increased, whereas extracellular dopamine is reduced (Yan et al, 2010), in the prefrontal cortex of NK1RÀ/À mice, compared with wildtypes. This disruption of monoaminergic transmission could increase inattentiveness (e.g.…”

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

“…First, as discussed in detail in Yan et al (2011), these monoamine transmitters modulate attention (Aston-Jones and Cohen, 2005), impulsivity (Cole and Robbins, 1987;Dalley and Roiser, 2012) and perseveration (Pioli et al, 2008). Secondly, their release is abnormal in NK1R-/-mice (Fisher et al, 2007;Froger et al, 2001;Herpfer et al, 2005). Thirdly, monoaminergic adaptation to challenging stimuli is well-known (e.g.…”

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

“…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).…”