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Disruption of noradrenergic transmission and the behavioural response to a novel environment in NK1R–/– mice
Author(s) -
Fisher Amy S.,
Stewart R. John,
Yan Ting,
Hunt Stephen P.,
Stanford S. Clare
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05369.x
Subject(s) - transmission (telecommunications) , neuroscience , psychology , environmental science , computer science , telecommunications
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 α 2 ‐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 α 2a ‐autoreceptors, which modulate noradrenergic transmission, is impaired in NK1R–/– mice. Consistent with this, [ 35 S]GTPγS binding to activated α 2a ‐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 α 2a ‐adrenoceptors. These changes could contribute to the difference in the behavioural phenotypes.