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.

Research in smoke inhalation has established that free radicals are produced from gases released during combustion and these species impair lung function. Using spin traps and their adducts in an animal model free radicals were measured. Various hyperbaric oxygen regimens were tested in an attempt to attenuate pulmonary damage caused by free radical reactions. Our data demonstrated that persistent oxygen- and carbon-centered free radicals are detectable in intravascular fluids after smoke inhalation. The smoke inhalation model showed however, clearing of spin trap adducts one hour after smoke exposure. Other researchers have found that when 100% oxygen is given at 1 atmosphere absolute (ATA) for 1 h, free radicals were not detectable. However, oxygen given at 2.5 ATA does produce detectable free radicals. With continued exposure at this pressure, the levels of free radicals increase for up to 60 min. This study suggests that the level of free radical induced oxygen toxicity may be a function of oxygen pressure and duration of oxygen exposure.

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