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Chronic atomoxetine treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats and alters markers of synaptic plasticity in the orbitofrontal cortex

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Abstract

Rationale

Impulsivity is a key symptom of attention-deficit hyperactivity disorder (ADHD). The use of the norepinephrine reuptake inhibitor, atomoxetine, to treat ADHD suggests that the activity of the norepinephrine transporter (NET) may be important in regulating impulsive behavior. Many ADHD patients receive chronic drug treatment during adolescence, a time when frontal brain regions important for impulse control are undergoing extensive development.

Objectives

The current study aimed to determine the effects of chronic atomoxetine treatment during adolescence in rats on two distinct forms of impulsivity in adulthood and whether any behavioral changes were accompanied by alterations in mRNA or protein levels within the frontal cortices.

Methods

Rats received daily injections of saline or atomoxetine (1 mg/kg) during adolescence (postnatal days 40–54). Two weeks later, animals were trained to perform either the delay-discounting test or the five-choice serial reaction time task (5CSRT).

Results

Adolescent atomoxetine treatment caused a stable decrease in selection of small immediate rewards over larger delayed rewards (impulsive choice) in adulthood, but did not affect premature responding (impulsive action) in the 5CSRT. Chronic atomoxetine treatment also altered the ability of acute atomoxetine to modulate aspects of impulsivity, but did not change the response to d-amphetamine. Ex vivo analysis of brain tissue indicated that chronic atomoxetine decreased phosphorylation of CREB and ERK in the orbitofrontal cortex and decreased mRNA for BDNF and cdk5.

Conclusions

These data suggest that repeated administration of atomoxetine in adolescence can lead to stable decreases in impulsive choice during adulthood, potentially via modulating development of the orbitofrontal cortex.

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Acknowledgements

This research was supported by a Discovery grant to CAW from the National Sciences and Engineering Research Council. CAW also receives salary support from the Michael Smith Foundation for Health Research and CIHR and an infrastructure grant from the Canadian Foundation for Innovation. HS was supported by two NSERC Undergraduate Student Research Awards. CAW has previously acted as a consultant for Theravance on an unrelated matter. No authors have any other conflicts of interest or financial disclosures to make.

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  1. HaoSheng Sun

    Present address: Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

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  1. Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada

    HaoSheng Sun, Paul J. Cocker, Fiona D. Zeeb & Catharine A. Winstanley

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  1. HaoSheng Sun
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  2. Paul J. Cocker
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Correspondence to Catharine A. Winstanley.

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Sun, H., Cocker, P.J., Zeeb, F.D. et al. Chronic atomoxetine treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats and alters markers of synaptic plasticity in the orbitofrontal cortex. Psychopharmacology 219, 285–301 (2012). https://doi.org/10.1007/s00213-011-2419-9

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