Hughes, Zoë A.; (1998) Modulation of extracellular noradrenaline in rat cortex by selective serotonin reuptake inhibitors (SSRIs). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This research project has investigated the modulation of central noradrenergic function in rat cortex by antidepressant drugs. Particular attention has been paid to the type of antidepressants known as the selective serotonin (5-HT) reuptake inhibitors (SSRIs). The therapeutic effects of these drugs are presently attributed exclusively to their inhibition of neuronal uptake of 5-HT. The aim of this work was to investigate whether the SSRIs, fluoxetine and citalopram, modify central noradrenergic function and, if so, was their site of action on noradrenergic neurones? In order to achieve this two techniques were used: the first used microdialysis to measure the concentration of extracellular noradrenaline in vivo, the second looked at the inhibition of [3H]noradrenaline uptake into rat cortical synaptosomes in vitro. In this thesis changes in the concentration of extracellular noradrenaline caused by local infusion of antidepressants in the frontal cortex of rats, were monitored using microdialysis. Fluoxetine and citalopram, as well as the noradrenaline uptake inhibitor, desipramine, increased noradrenaline efflux. To investigate whether inhibition of noradrenaline uptake could contribute to this increase in efflux, the effects of these drugs on synaptosomal [3H]noradrenaline uptake were studied. Because these drugs inhibit [3H]noradrenaline uptake, it is likely that inhibition of noradrenaline uptake contributes to the increase in noradrenaline efflux in vivo. In view of this finding, the possible site(s) of action of these drugs were investigated. An uptake site targeted by SSRIs could be located on serotonergic neurones. The 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), was used as a tool to investigate this possibility. Because a selective lesion of 5-HT neurones did not affect the inhibition of [3H]noradrenaline uptake by any of the drugs, it is unlikely that fluoxetine, citalopram or desipramine were acting at a site on serotonergic neurones. The second possible site of action investigated was one located on noradrenergic neurones. Pretreatment of rats with the noradrenergic neurotoxin, N-(2-chloroethyl)-N-etiyl-2-broinobenzylamine (DSP-4), modified the effects of these antidepressants on noradrenergic function. Low concentrations of desipramine inhibited a smaller proportion of [3H]noradrenaline uptake than in control rats. In contrast, a greater proportion of uptake in the cortex of DSP-4 lesioned rats was sensitive to inhibition by low concentrations of fluoxetine in vitro. The effects of these drugs on noradrenaline efflux in vivo were also changed after DSP-4 pretreatment. The increase in noradrenaline efflux induced by desipramine was greater in DSP-4 treated rats, whereas the fluoxetine-induced increase, apparent in control rats, was not evident after DSP-4. The effects of citalopram were unaffected by DSP-4 treatment, suggesting that SSRIs do not all have the same pharmacological profile and that fluoxetine, but not citalopram, could act at a site on noradrenergic neurones. One additional, but important finding to emerge from work described in this thesis was that, although DSP-4 treatment caused a 70% reduction in tissue noradrenaline content, the concentration of extracellular noradrenaline was increased nearly 2-fold. Results suggest that neurones which survive DSP-4 treatment have a greater rate of noradrenaline release, moreover, released noradrenaline is taken up via low affinity uptake sites. Overall, the experiments in this thesis have exposed marked effects of SSRIs on central noradrenergic function which could contribute to the efficacy of antidepressants hitherto regarded as acting selectively on serotonergic neurones.

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