Investigation of a role for noradrenaline in the neurochemical and behavioural effects of an established and putative target for antianxiety I antidepressant drugs: a microdialysis and behavioural study in rats and NK1 receptor knockout mice

The precise neurochemical effects of antidepressants that underlie their efficacy remain unclear. Many antidepressants modulate noradrenaline transmission in vivo. However, the selective serotonin reuptake inhibitors (SSRIs) and NK1 receptor antagonists target 5-HT and substance P transmission, respectively. Whether effects on noradrenaline neurones contribute to the efficacy of these drugs has been largely neglected. This study investigates modulation of central NA transmission by an SSRI (fluoxetine) in rats and by NK1 receptor ablation in mice. NK1 ‘knockout’ mice are used as a model for lifelong inhibition of the NK1 receptor. Changes in noradrenaline transmission were determined using in vivo microdialysis to sample the extracellular noradrenaline concentration (efflux). Noradrenaline-related behavioural effects of these treatments were determined using a modified light/dark exploration test. Systemic fluoxetine increased noradrenaline efflux in two brain regions (frontal cortex and hypothalamus). The effect was inconsistent, echoing the 5-HT response to SSRIs. Fluoxetine reduced noradrenaline efflux after partial lesioning of noradrenergic axon terminals (by DSP-4), suggesting an inhibitory action upstream of these terminals. Locally infused (retrodialysis) fluoxetine augmented noradrenaline efflux in the terminal field. Whereas 50pM fluoxetine elevated efflux in both regions, 5pM infusion increased efflux in the frontal cortex only. This effect was 5-HT-dependent (i.e. 5-HT synthesis inhibition with pCPA blocked the response). However, this increase was not secondary to inhibition of 5-HT reuptake (since the more potent and selective SSRI, citalopram, did not change noradrenaline efflux). Thus, fluoxetine has opposing effects on noradrenaline efflux, probably at cell bodies and terminals. The balance of processes could underlie its variable effects. Fluoxetine reduced locomotor activity of DSP-4-pretreated rats in the novel compartment of the exploration box, suggesting a noradrenaline-related effect on behaviour. A 5-HT-related effect of fluoxetine was also found (reduced locomotor activity in the dark compartment), since this was abolished by pCPA.