Fisher, A.S.; (2006) Noradrenergic function in NK1+/+ and NK1-/- mice. Doctoral thesis , University of London.

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Abstract

NK1 receptor antagonists represent an emerging class of putative antidepressants. These compounds may act through an interaction with 5-HT and / or noradrenaline (NA), the targets of established antidepressants. Pilot microdialysis studies in our laboratory have demonstrated that cortical NA efflux is 2-fold higher in halothane-anaesthetised NK1-/- mice compared with NK1+/+ mice. These current studies were, therefore, primarily aimed at investigating the autoregulatory 012-adrenoceptor, which controls the firing-rate and release of NA from noradrenergic neurones. NA efflux was monitored following systemic administration of the -adrenoceptor antagonist RX821002, during anaesthetised (0.3 mg /kg i.p.), and freely-moving (0.3, 1.0 and 3.0 mg / kg i.p.), in vivo microdialysis. NA efflux and the behavioural response to an aversive, naturalistic stimulus were investigated using the light / dark exploration box (LDEB), in naive and RX821002 pre-treated mice. Localisation and density of -adrenoceptors were examined using immunohistochemistry, Western blot analysis and 3H RX821002 autoradiography. Adrenaline-stimulated 35S GTPyS binding analysed the functional status of the a2-adrenoceptors. Basal NA efflux was 4-5-fold higher in halothane-anaesthetised NK1-/- mice compared with NK1+/+ mice. No difference in NA efflux between genotypes was found during freely-moving mouse microdialysis. Treatment with RX821002, increased NA efflux in NK1+/+ mice, only. Of the 12 behaviours scored in the LDEB, 5 were genotype dependent. With the exception of rearing activity, these were not dependent on the genotype difference in locomotor activity. In the LDEB pre-treatment with RX821002 modified the behavioural response in 4 of the 12 behaviours, and increased NA efflux in NK1+/+ mice, only. However, no difference in net NA efflux was found between groups. No difference between NK1+/+ and NK1-/- mice in the localisation, density or functional activity of the a2-adrenoceptors was found. These results suggest that genetic disruption of the NK1 receptor, modifies the regulation of the noradrenergic system, which can, at least in part, be attributed to a decreased sensitivity of the -adrenoceptor.

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