Abstract
RationaleAtomoxetine is a noradrenaline re-uptake inhibitor licensed for the treatment of adult and childhood attention deficit hyperactivity disorder. Although atomoxetine has established efficacy, the mechanisms which mediate its effects are not well understood.ObjectivesIn this study, we investigated the role of cortical versus sub-cortical noradrenaline by using focal dopamine beta hydroxylase-saporin-induced lesions, to the prefrontal cortex (n = 16) or nucleus accumbens shell (n = 18).MethodsHealthy animals were tested by using the forced-choice serial reaction time task to assess the impact of the lesion on baseline performance and the response to atomoxetine and the psychostimulant amphetamine.ResultsWe observed attenuation in the efficacy of atomoxetine in animals with lesions to the nucleus accumbens shell, but not the prefrontal cortex. Amphetamine-induced increases in premature responses were potentiated in animals with lesions to the prefrontal cortex, but not the nucleus accumbens shell.ConclusionsThese data suggest that noradrenaline in the nucleus accumbens shell plays an important role in the effects of atomoxetine. Under these conditions, prefrontal cortex noradrenaline did not appear to contribute to atomoxetine’s effects suggesting a lack of cortical-mediated “top-down” modulation. Noradrenaline in the prefrontal cortex appears to contribute to the modulation of impulsive responding in amphetamine-treated animals, with a loss of noradrenaline associated with potentiation of its effects. These data demonstrate a potential dissociation between cortical and sub-cortical noradrenergic mechanisms and impulse control in terms of the actions of atomoxetine and amphetamine.
Highlights
Atomoxetine is a noradrenaline re-uptake inhibitor licensed for the treatment of adult and childhood attention deficit hyperactivity disorder (Christman et al 2004; Michelson et al 2002)
Noradrenaline in the prefrontal cortex appears to contribute to the modulation of impulsive responding in amphetamine-treated animals, with a loss of noradrenaline associated with potentiation of its effects
There were no differences between sham and lesion animals across performance variables for either prefrontal cortex (PFC) or nucleus accumbens shell (NAcSh) cohorts (Table S1) confirming that groups were matched prior to surgery, and lesions had no effect on baseline performance
Summary
Atomoxetine is a noradrenaline re-uptake inhibitor licensed for the treatment of adult and childhood attention deficit hyperactivity disorder (Christman et al 2004; Michelson et al 2002). In both receptor binding studies and in vivo functional characterization, atomoxetine has been shown to have a relatively selective effect on the noradrenaline transporter (NAT) versus either the dopamine active transporter (DAT) or serotonin transporter (SERT) (Bymaster et al 2002; Seneca et al 2006; Somkuwar et al 2013), see Ding et al (2014) in relation to SERT occupancy.
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