Sun H, Cocker PJ, Zeeb FD, Winstanley CA. 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 (Berl) 219: 285-301

Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada.
Psychopharmacology (Impact Factor: 3.88). 08/2011; 219(2):285-301. DOI: 10.1007/s00213-011-2419-9
Source: PubMed


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.
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.
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).
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.
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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Available from: Catharine A Winstanley, Apr 20, 2015
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    • "For example, using a dosage equivalent to the clinical treatment (i.e., 1 mg/kg), the increase of prefrontal norepinephrine induced by atomoxetine was reduced by chronic administration (Koda et al., 2010). This finding agrees with the observation that chronic atomoxetine exposure increases norepinephrine transporter mRNA, while decreasing markers of synaptic plasticity (Sun et al., 2012). "
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    ABSTRACT: Methylphenidate and atomoxetine are effective in treating attention-deficit/hyperactivity disorder (ADHD) with underlying distinct pharmacological mechanisms. To relate neural mechanisms to clinical response, we conducted a comparative trial to differentiate the changes in brain activation of drug-naïve children with ADHD when performing neuropsychological tasks after 12 weeks of pharmacotherapy. We randomized 50 drug-naïve children with ADHD, aged 7-17, to treatment with methylphenidate (n=25) or atomoxetine (n=25). These children were scanned twice with functional magnetic resonance imaging (fMRI) during the counting Stroop task before and after treatment. Focused attention and impulsivity were assessed twice by using the Conner's Continuous Performance Test (CCPT). The final sample for fMRI analysis comprised 20 in the methylphenidate group and 22 in the atomoxetine group. Atomoxetine decreased activations in the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex, which correlated with improvement in focused attention assessed by the CCPT. In contrast, methylphenidate increased activations in the inferior frontal gyrus, which correlated with the decreasing severity of impulsivity assessed by the CCPT. The current findings suggest that differential therapeutic effects on neuronal changes induced by 12-week treatment atomoxetine and methylphenidate may contribute to behavioral improvement.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2015; DOI:10.1016/j.euroneuro.2015.08.024 · 4.37 Impact Factor
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    • "Finally, successful use of the location rule also requires inhibition of the pre-potent motor response into the illuminated port. However, it is unlikely that atomoxetine affected this process given that atomoxetine does not affect motor impulsivity (Sun et al. 2011). In our task, the latency to respond was not affected by atomoxetine, which also suggests that prepotent motor responses were not affected by the drug. "
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    ABSTRACT: 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.
    Psychopharmacology 07/2015; 232(20). DOI:10.1007/s00213-015-4028-5 · 3.88 Impact Factor
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    • "There are isolated reports that atomoxetine improves accuracy in rats (Baarendse and Vanderschuren, 2012; Robinson, 2012) but, in general, %omissions in the 5-CSRTT increase, rather than diminish, after atomoxetine treatment (e.g. Baarendse and Vanderschuren, 2012; Sun et al., 2012). However, inattentiveness is consistently reduced by atomoxetine in clinical studies (Faraone and Glatt, 2010; Hazell et al., 2011; Wilens et al., 2006), suggesting that this aspect of behaviour in the 5-CSRTT might not translate reliably between rodents and humans. "
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    ABSTRACT: Background Mice with functional ablation of the neurokinin-1 receptor gene (NK1R −/−) display behavioral abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT). Methods Separate cohorts of mice were tested in the 5-CSRTT and LDEB after treatment with no injection, vehicle or atomoxetine (5CSRTT: 0.3, 3 or 10 mg/kg; LDEB: 1, 3 or 10 mg/kg). Results Atomoxetine reduced the hyperactivity displayed by NK1R −/− mice in the LDEB at a dose (3 mg/kg) which did not affect the locomotor activity of wildtypes. Atomoxetine (10 mg/kg) also reduced impulsivity in NK1R −/− mice, but not wildtypes, in the 5-CSRTT. No dose of drug affected attention in either genotype. Conclusions This evidence that atomoxetine reduces hyperactive/impulsive behaviors in NK1R −/− mice consolidates the validity of using NK1R −/− mice in research of the aetiology and treatment of ADHD.
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