Mason, Kathryn; (1997) Modulation of central noradrenaline efflux by pharmacological and novel environmental stimuli: A microdialysis study. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Central noradrenergic neurones are widely believed to be involved in anxiety and the response to stress. The present experiments investigated these links further using microdialysis in vivo to monitor changes in central monoamine efflux. In general, noradrenaline efflux in rat frontal cortex, a limbic region, was the focus of investigation. Dopamine efflux in the nucleus accumbens, another limbic region, was also investigated in one set of experiments. First, experiments confirmed that noradrenaline release was derived from neurones by exocytosis. Then, the effects of established anxiolytic (flurazepam) or anxiogenic (yohimbine or FG7142) agents, on spontaneous efflux of noradrenaline were investigated. Systemic injection of flurazepam reduced the spontaneous efflux of noradrenaline in the frontal cortex. However, despite its evident diffusion across the dialysis membrane, local administration of flurazepam via the probe did not modify the efflux of noradrenaline. To investigate this further, experiments attempted to reproduce published evidence that local perfusion of flurazepam attenuates the efflux of dopamine in the nucleus accumbens. However, neither local, nor systemic administration of flurazepam affected the efflux of dopamine in the core zone of this brain region. In light of recent evidence, it is possible that this is because the core of the nucleus accumbens is less sensitive to the effects of flurazepam than is the shell zone and that different studies have examined different zones. This needs further investigation, but was regarded as being beyond the scope of the project. In contrast to flurazepam, yohimbine increased the efflux of noradrenaline in the frontal cortex while FG7142 was without effect, at doses with established anxiogenic effects. The next experiments investigated the effect of flurazepam on the yohimbine-induced increase in noradrenaline efflux. It was found that systemic injection of flurazepam, but not its local application via the probe, significantly attenuated the efflux of noradrenaline when this was elevated by yohimbine. Flurazepam also reduced the net increase in efflux caused by yohimbine, i.e. it blunted the noradrenergic response to this drug. Since these effects of flurazepam were evident only after systemic administration, it is unlikely that they involve processes in the terminal field. Finally, the effect of yohimbine or FG7142 on the noradrenergic response to the stress of exposure to a novel environment was investigated. This form of stress, used routinely in animal models of anxiety, increased the efflux of noradrenaline. Although yohimbine increased the underlying efflux of noradrenaline in both stressed and non-stressed rats, the net efflux during stress was significantly less than in vehicle-injected controls. In contrast. FG7142, which did not modify the underlying efflux of noradrenaline, increased the net efflux of noradrenaline during stress. Therefore, yohimbine blunted the noradrenergic response to stress, whereas FG7142 increased it. Collectively the results suggest that the anxiolytic, flurazepam, attenuates the increase in noradrenaline efflux caused by the generically unrelated anxiogenic agent, yohimbine. The results also indicate that anxiogenic agents can have inconsistent effects on the noradrenergic response to stress (i.e. the net efflux). Moreover, their effects on the stress response cannot be predicted from their effects in unstressed subjects. It is hypothesized that net efflux during stress determines the coping response and that any deviation from the optimum efflux provokes anxiety.

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