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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    • "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.
    Pharmacology Biochemistry and Behavior 10/2014; 127. DOI:10.1016/j.pbb.2014.10.008 · 2.78 Impact Factor
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    • "Norepinephrine in the PFC modulates cognitive functioning and has been associated with attention regulation, working memory, and behavioral inhibition (Arnsten 2000; Arnsten and Casey 2011). While results examining the effects of DA receptor agonists and antagonists on delay discounting have been mixed (Hamidovic et al. 2008; Wade et al. 2000; van Gaalen et al. 2006), previous work found decreased impulsive choice during a delay-discounting task with NET inhibition by ATO (Bizot et al. 2011; Robinson et al. 2008, but see Baarendse and Vanderschuren 2012; Broos et al. 2012a, b; Sun et al. 2012). Exercise also increases extracellular levels of NE and DA in the PFC (Ma 2008; Meeusen and De Meirleir 1995; Paluska and Schwenk 2000), and it may be by this mechanism that wheel running augmented the treatment effects of ATO and resulted in differential levels of wheel running in LoI versus HiI rats. "
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    ABSTRACT: Background: Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement of cocaine-seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO versus each treatment alone on cocaine-seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive). Methods: Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine-seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO). Results: HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared with vehicle treatment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treatment effects. Conclusions: These findings demonstrated greater attenuation of cue- versus cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.
    Psychopharmacology 09/2014; 232(6). DOI:10.1007/s00213-014-3744-6 · 3.88 Impact Factor
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    • "). Developmental studies with rats have found that chronic treatment with atomoxetine (Sun et al., 2012) and corticosterone (Torregrossa et al., 2012) during adolescence and social isolation during infancy (Lovic et al., 2011a) have differential effects on action and cognitive impulsivity. A drug abuse related study reported that action impulsivity was associated with nicotine self-administration while cognitive impulsivity was associated with enhanced vulnerability to relapse (Diergaarde et al., 2008). "
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    ABSTRACT: Due in part to their rich behavioral repertoire rats have been widely used in behavioral studies of drug abuse-related traits for decades. However, the mouse became the model of choice for researchers exploring the genetic underpinnings of addiction after the first mouse study was published demonstrating the capability of engineering the mouse genome through embryonic stem cell technology. The sequencing of the mouse genome and more recent re-sequencing of numerous inbred mouse strains have further cemented the status of mice as the premier mammalian organism for genetic studies. As a result, many of the behavioral paradigms initially developed and optimized for rats have been adapted to mice. However, numerous complex and interesting drug abuse-related behaviors that can be studied in rats are very difficult or impossible to adapt for use in mice, impeding the genetic dissection of those traits. Now, technological advances have removed many of the historical limitations of genetic studies in rats. For instance, the rat genome has been sequenced and many inbred rat strains are now being re-sequenced and outbred rat stocks are being used to fine-map QTLs. In addition, it is now possible to create "knockout" rats using zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs) and related techniques. Thus, rats can now be used to perform quantitative genetic studies of sophisticated behaviors that have been difficult or impossible to study in mice. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
    Neuropharmacology 06/2013; 76. DOI:10.1016/j.neuropharm.2013.05.047 · 5.11 Impact Factor
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