Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat

Abstract

Rationale: Atomoxetine 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.

Objectives: In 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).

Methods: Healthy 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.

Results: We 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.

Conclusions: These 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.

Keywords: Amphetamine; Atomoxetine; Impulse control; Noradrenaline; Nucleus accumbens; Prefrontal cortex.

Fig. 1

F-CSRTT trial sequence. Schematic illustrating the sequence of events for correct, omission, and premature trial types in the F-CSRTT, adapted from Bari et al. (2008)

Fig. 2

DβH immunostaining and lesion assessment. Representative images from the PFC (a) and NAcSh (b) showing reduced DβH fiber staining following DβH saporin lesions versus sham controls. Images shown are from the PL and NAcSh, scale bar = 50 μm; black square indicates approximate location on brain atlas. Lesion assessment summary (c) expressed as the percentage of DβH immunostaining compared to sham controls, see Table S2 for full list of brain regions analyzed. PFC (sham n = 8, lesion n = 8) and NAcSh (sham n = 9, lesion n = 9), *p < 0.05 sham versus lesion, within subject. CC corpus callosum, Cg1 cingulate cortex 1, Cg2 cingulate cortex 2, CPu caudate putamen, DβH dopamine beta hydroxylase, DLO dorsolateral orbital cortex, IL infralimbic, LO lateral orbital cortex, LV lateral ventricle, M1 motor cortex, M2 motor cortex, MO medial orbital cortex, NAcC nucleus accumbens core, NAcSh nucleus accumbens shell, PL prelimbic, PRh perirhinal cortex, VO ventral orbital cortex

Fig. 3

Atomoxetine dose response. The effects of atomoxetine (0.0–3.0 mg/kg) on F-CSRTT performance in animals with PFC (a) or NAcSh (b) noradrenergic lesions. Results are shown for the total population, mean ± SEM, n = 16 (PFC lesions) and n = 18 (NAcSh lesions) animals per group. *p < 0.05, **p < 0.01, ***p < 0.001, versus vehicle (within subject)

Fig. 4

Amphetamine dose response. The effects of amphetamine (0.0–1.0 mg/kg) on F-CSRTT performance in animals with PFC (a) or NAcSh (b) noradrenergic lesions. Results are shown for the total population, mean ± SEM, n = 15 (PFC lesions) and n = 17 (NAcSh lesions) animals per group. *p < 0.05, **p < 0.01, ***p < 0.001, versus vehicle (within subject); #p < 0.05 versus sham (between subject)