NK1 receptor antagonists are putatively a novel class of anxiolytic/antidepressant drugs (Kramer et al, 1998). All established antidepressants modify noradrenergic transmission in vivo. Here, our aim was to discover whether central noradrenergic (NA) transmission is modified by disruption of expression of the NK1 receptor gene and whether this could affect mood and behaviour.

We used in vivo microdialysis to compare NA efflux in the frontal cortex of halothane-anaesthetised adult male NK1-/- and NK1+/+ mice. In order to investigate apparent differences in basal efflux, we tested the effects of systemic administration of the a2-adrenoceptor antagonist, atipamezole (3mg kg^-1i.p.) and, 80 min later, local infusion (via the probe) of the NA reuptake inhibitor, desipramine (DMI; 5µM). In parallel experiments, the behaviour of NK1-/- and NK1+/+ mice, given either atipamezole or saline, was compared in a light-dark shuttle-box (LDSB) (see McQuade et al., 1999). Results were analysed by ANOVA with a post hoc least squares test.

Basal efflux of NA was 2-fold greater in NK1-/- (20±1.3 fmoles 20min^-1) than in NK1+/+ mice (9.0±0.5 fmoles 20min^-1) (main effect of 'genotype': F_1,21=5.1; P=0.04). Atipamezole did not affect NA efflux in either NK1-/- or NK1+/+ mice. On subsequent infusion of DMI, the incremental increase in NA efflux was similar in the two strains (NK1-/-: 6.7±1.2 fmoles 20min^-1; NK1+/+: 5.4±1.0 fmoles 20min^-1; main effect of 'time': F_11,132=3.9, P<0.001).

The efflux of noradrenaline reflects a steady-state between its release and reuptake. Because reuptake of NA did not differ in NK1-/- and NK1+/+ mice, the difference in basal efflux of NA is most likely explained by an increase in NA release in NK1-/- mice. The lack of effect of atipamezole on NA efflux suggests that activation of a2-autoreceptors has a negligible effect on NA release in either group of mice. In NK1+/+ mice, this could be because there is little tonic activation of ₂-autoreceptors. The lack of any effects of atipamezole in NK1-/- mice, despite an increased basal efflux, suggests that the function of their 2-autoreceptors is impaired.

In the LDSB, NK1 receptor ablation increased 'locomotor activity in the light arena' (F_1,36=5.8, P=0.02) but reduced 'rears in the dark arena' (F_1,36=7.5; P=0.01). Atipamezole increased the 'number of returns to the light arena' (F_1,36 =7.9; P<0.01). However, there was a 'genotype' x 'drug treatment' interaction for 'latency to leave the light arena' (F_1,36 =4.1; P<0.05) and 'time to return' to the light arena (F_1,36=4.7, P<0.05). In both cases, atipamezole had no significant effect in NK1-/- mice, which resembled NK1+/+ mice that had been treated with this antagonist.

We conclude that ablation of NK1 receptors is associated with an increase in NA efflux and blunting of the effects of the a2-adrenoceptor antagonist, atipamezole, on certain behaviours in the LDSB. The possibility that these changes are explained by a deficit in the function of presynaptic and/or postsynaptic a2-adrenoceptors in NK1-/- mice is under investigation.

Kramer et al., (1998) Science 281:1640-45.
McQuade et al., (1999) Psychopharmacology 145:393-400.