| pA2 online © Copyright 2004 The British Pharmacological Society |
134P
GKT, University of London Winter Meeting December 2003 |
|
The effect
of the antidepressant desipramine on noradrenaline efflux and behaviour
of NK1-/- and NK1+/+ mice |
|
Print abstractA range of behaviours of mice, in which the expression of the substance P-preferring tachykinin NK1 receptor has been disrupted (NK1-/-), resemble those of the wildtype (NK1+/+) after administration of antidepressant or anxiolytic drugs (Rupniak et al., 2001; Santarelli et al., 2001). Increased central noradrenergic (NA) transmission has long been linked with the therapeutic effects of antidepressants. The aim of this study was to investigate whether there could be increased NA transmission in NK1-/- mice, and whether this could contribute to their altered behaviour.
Male NK1-/- and NK1+/+ mice (25-31g), derived from 129/Sv x C57BL/6, back-crossed against MF1 mice, were used. Efflux of NA in the frontal cortex of halothane-anaesthetised animals was monitored using in vivo microdialysis and HPLC-ECD. In parallel studies, we compared the behaviour of the two genotypes in a modified light/dark shuttle-box (LDSB), as described in McQuade et al. (1999). Desipramine (DMI), an established tricyclic antidepressant, with high selectivity for blockade of the NA transporter, was administered (10 mg kg-1, 10 ml kg-1, i.p.) either 80 min after start of microdialysis or 30 min before behavioural observations
Mean basal efflux of NA in NK1-/- mice was 4.6-fold greater than in their NK1+/+ counterparts (17.0 ± 3.1 fmol 20 min-1 vs. 3.7 ± 1.1 fmol 20 min-1, respectively, F1,17=18.1, P=0.001). The peak NA efflux, 100 min after DMI injection, in NK1-/- mice (n=7, 32.1 ± 7.0 fmol 20 min-1) was 2.4-fold higher than in NK1+/+ (n=7, 13.3 ± 3.7 fmol 20 min-1), but the net increase did not differ between the genotypes.
| Treatment group |
NK1+/+
vehicle
|
NK1-/-
vehicle
|
NK1+/+
DMI
|
NK1-/-
DMI
|
| Line crosses *· |
212.9
± 46.2
|
407.4
± 69.8
|
108.4
± 26.2
|
107.0 ± 17.0
|
| Grooming (S) **·· |
147.3
± 56.4
|
480.0
± 63.1
|
86.6
± 36.6
|
131.3
± 42.2
|
| SAP ** |
50.4
± 11.6
|
7.7
± 0.9
|
32.3
± 5.6
|
9.1
± 2.0
|
| FBA (S) ** |
99.4
± 20.5
|
10.7
± 2.8
|
96.4
± 22.3
|
23.6 ± 7.9
|
| Time to first return (S) * |
70.3
± 29.1
|
32.1
± 11.7
|
47.0
± 9.7
|
23.2
± 2.6
|
| Time in light (S) * |
580.4
± 204.8
|
359.0
± 113.4
|
677.0
± 292.2
|
131.3
± 23.7
|
Values show mean ± s.e.mean. N=7 per group. ANOVA: main effect of 'genotype': *p£0.05, **p<0.01; 'drug x genotype' interaction: ·p<0.05, ··p<0.01.
As regards their behaviour in the LDSB (see Table 1 for key changes), when compared with NK1+/+ mice, NK1-/- mice showed higher scores for locomotor activity (line crosses) and grooming but lower scores for risk assessment (stretched-attend postures, SAP; flat-back approach, FBA; time to return) and time spent in the light zone. The reduction in risk assessment behaviour in NK1-/- was not influenced by DMI, whereas the difference in their activity and grooming was reduced, or abolished, by DMI.
The microdialysis findings support our hypothesis that central noradrenergic transmission is increased in NK1-/- mice and this could contribute to the differences in their behaviour compared with the NK1+/+ wildtype.
McQuade et al. (1999)
Psychopharmacology 145, 393-400.
Rupniak et al. (2001) Behav Pharmacol 12, 497-508.
Santarelli et al. (2001) Proc Natl Acad Sci USA 98, 1912-17.