Atomoxetine accelerates attentional set shifting without affecting learning rate in the rat



Shifting to a new rule is a form of behavioral flexibility that is impaired in numerous psychiatric and neurological illnesses. Animal studies have revealed that this form of flexibility depends upon norepinephrine (NE) neurotransmission. Atomoxetine, a NE reuptake inhibitor, improves performance of humans in set shifting tasks.


Our objective was to validate its effects in a rodent set shifting task.


We tested the drug effect using an operant task that required a shift from a visual cue-guided behavior to a novel location-guided rule.


A 1.0-mg/kg dose significantly accelerated rule shifting without affecting learning strategies, such as win-stay or lose-shift. Fitting behavioral performance with a learning function provided a measure of learning rate.


This novel analysis revealed that atomoxetine accelerated shifting to the new rule without affecting learning rate.

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We thank G. Katakalidis and D. Vasilyev for training animals. We also thank A. Dwarakanath for the technical assistance with the psigfit MATLAB toolbox.


This work was funded by a Marie Curie fellowship to N.K.T. (PIIF-GA-2012-331122) in the European Union FP7 funding scheme and the Max Planck Society.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Correspondence to Nelson K. Totah.

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Figure S1

Individual switch point, slope, and fits for all rats in the study. A. The fit of the performance for each rat is plotted for each drug dose and each size of trial block. The top panel is the high dose, the middle panel the low dose, and the bottom panel is vehicle (control). Each column is labeled with the number of trials used in a block for calculating performance. Individual rats are plotted in differently colored lines and the legend contains the rat identification number. B. The switch point acquired from the performance fits of each rat (above) are plotted according to the drug dose. Rats which were outliers are marked in red with their identification number. As in A, the columns are labeled with the number of trials used in a block for calculating performance. Note that the same rat (r1052), which received 1.0 mg/kg atomoxetine, was an outlier for all block sizes used to calculate performance. The top panel of A shows the performance of this rat as a purple line. (GIF 127 kb)

Table S1

The percent of trials that were correct responses and omissions for each rule are shown as an SEM for each drug dose. The light cue-guided session was preceded by a saline injection for all rats, while the location-based session was preceded by the drug injection. Omissions for both rules and all drug doses were low. (XLSX 11 kb)

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Totah, N.K., Logothetis, N.K. & Eschenko, O. Atomoxetine accelerates attentional set shifting without affecting learning rate in the rat. Psychopharmacology 232, 3697–3707 (2015) doi:10.1007/s00213-015-4028-5

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  • Attention
  • Learning
  • Set-shifting
  • Behavioral flexibility
  • Rat
  • Norepinephrine
  • Prefrontal cortex
  • ADHD
  • Schizophrenia