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

Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada.
Psychopharmacology (Impact Factor: 3.99). 08/2011; 219(2):285-301. DOI: 10.1007/s00213-011-2419-9
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cdk5 has been implicated in a multitude of processes in neuronal development, cell biology and physiology. These influence many neurological disorders, but the very breadth of Cdk5 effects has made it difficult to synthesize a coherent picture of the part played by this protein in health and disease. In this review, we focus on the roles of Cdk5 in neuronal function, particularly synaptic homeostasis, plasticity, neurotransmission, subcellular organization, and trafficking. We then discuss how disruption of these Cdk5 activities may initiate or exacerbate neural disorders. A recurring theme will be the sensitivity of Cdk5 sequelae to the precise biological context under consideration.
    07/2012; 2012(Suppl 1):001. DOI:10.4172/2168-975X.S1-001
  • Source
    [Show abstract] [Hide abstract]
    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 · 2.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although a multifaceted concept, many forms of impulsivity may originate from interactions between prefrontally-mediated cognitive control mechanisms and limbic, reward or incentive salience approach processes. We describe a novel task that combines reward and control processes to probe this putative interaction. The task involves elements of the monetary incentive delay task (Knutson et al., [2000]: Neuroimage 12:20-27) and the Go/No-Go task (Garavan et al., [1999]: Neuroimage 17:1820-1829) and requires human subjects to make fast responses to targets for financial reward but to occasionally inhibit responding when a NoGo signal rather than a target is presented. In elucidating the dynamic between reward anticipation and control we observed that successful inhibitions on monetary trials, relative to unsuccessful inhibitions, were associated, during the anticipation phase, with increased activation in the right inferior frontal gyrus (rIFG), decreased activity in the ventral striatum (VS), and altered functional connectivity between the two. Notably, this rIFG area had a small overlap but was largely distinct from an adjacent rIFG region that was active for the subsequent motor response inhibitions. Combined, the results suggest a role for adjacent regions of the rIFG in impulsive choice and in impulsive responding and identify a functional coupling between the rIFG and the VS. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 08/2014; 36(1). DOI:10.1002/hbm.22621 · 6.92 Impact Factor


Available from