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Title: Modulation of central noradrenergic function by the anti-obesity agent, sibutramine
Author: Wortley, Katherine Emily
ISNI:       0000 0001 3572 8622
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2000
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The active metabolites of the anti-obesity agent, sibutramine, inhibit the reuptake of noradrenaline in vitro. The first aim of this project was to establish whether sibutramine also increases central extracellular noradrenaline concentration in vivo and, if so, whether this effect can be distinguished from that of the anti-obesity agent, (^-amphetamine, which is a noradrenaline-releasing agent. Changes in extracellular noradrenaline concentration were measured using in vivo microdialysis in rat frontal cortex or hypothalamus. Since presynaptic oci-adrenoceptors regulate noradrenergic neuronal activity, the role of these receptors in modulating extracellular noradrenaline concentration following sibutramine or (^-amphetamine administration was investigated. The second aim was to investigate the density and function of az-adrenoceptors in the lean and obese Zucker rat in order to determine whether an abnormality in central noradrenergic systems existed in the obese state. The density of (%2-adrenoceptors in the cortex and hypothalamus were investigated using radioligand binding studies. The functions of pre- and post-synaptic az-adrenoceptors were investigated using clonidine-induced hypoactivity and mydriasis, respectively. Sibutramine induced a gradual increase in extracellular noradrenaline concentration in the cortex of anaesthetised rats whereas (i-amphetamine induced a rapid increase. Blockade of ocz-adrenoceptors with the antagonist, RX821002, enhanced the sibutramine-induced increase in extracellular noradrenaline by 5-fold but enhanced the effect of ^/-amphetamine by only 2-fold. Sibutramine also increased extracellular noradrenaline concentration in the cortex and hypothalamus of freely-moving rats although this effect declined in the hypothalamus 40 min post-injection. Reverse dialysis of RX821002 into the cortex or hypothalamus enhanced the sibutramine-induced increase in extracellular noradrenaline in these areas and reversed the decline in extracellular noradrenaline in the hypothalamus 40 min after sibutramine administration. This indicates that central az-adrenoceptors restrict the accumulation of extracellular noradrenaline induced by sibutramine, but that this effect is greater in the hypothalamus. No differences in the density of [^H]RX821002 binding sites or post-synaptic OEz-adrenoceptor function were found between lean and obese Zucker rats. However, the affinity of az-adrenoceptors for [^H]RX821002 in the cortex of obese rats was higher compared with lean rats. Obese rats also had a higher hypoactivity score under drug-free conditions than did lean rats. Furthermore, the increase in hypoactivity score induced by clonidine in lean Zucker rats reached a plateau between 0.1-0.3 mg / kg, whereas obese rats showed no sign of reaching a plateau at these doses. All these findings indicate that presynaptic az-adrenoceptor function is enhanced in obese Zucker rats. The findings of this thesis show that the increase in extracellular noradrenaline concentration induced by sibutramine in vivo can be differentiated from that of ^/-amphetamine. However, the time-course of sibutramine’s effect varies in different brain regions depending on the density and/or function of a 2-adrenoceptors. Finally, the function of presynaptic a 2-adrenoceptors appears to be enhanced in obese Zucker rats, possibly due to an increased affinity of these receptors for a 2-adrenoceptor ligands. This finding suggests that central noradrenergic activity could be impaired in obese Zucker rats.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry