, Volume 236, Issue 12, pp 3579–3592 | Cite as

The use of reaction time distributions to study attention in male rats: the effects of atomoxetine and guanfacine

  • Zach V. Redding
  • Pooja Chawla
  • Karen E. SabolEmail author
Original Investigation



Norepinephrine (NE) is involved in the control of sustained attention. Studies of sustained attention in humans include measures of reaction time (RT) and RT variability (RTV). The present study tested the role of NE using components of the RT distribution in rats in a manner thought to be similar to human studies of RTV.


This study tested the effects of increased synaptic NE (atomoxetine (ATX)) and α-2 receptor binding (guanfacine) on attentional lapses in rats.


Male Sprague-Dawley rats (n = 20) were trained and tested in a two-choice RT task (2CRTT). Atomoxetine dose (saline, 0.1, 0.5, 1.0 mg/kg, i.p.), guanfacine dose (saline, 0.01, 0.1, 0.3 mg/kg, i.p.), and distractors were manipulated in three experiments. RT was divided into initiation time (IT) and movement time (MT). Analyses of distribution mode (peak) and deviation from the mode (skew) were then performed.


ATX and guanfacine had no effect on IT mode, reduced IT devmode, and increased MT mode. When distractors were introduced, ATX again improved devmode, but a lack of interaction between ATX and distractor indicated that ATX did not prevent distractor-induced impairments.


IT devmode is a measure of distribution skew thought to reflect lapses of attention. The effects of ATX on IT devmode suggest that increased synaptic NE reduces attentional lapses. These findings are consistent with human reports of reduced RTV after ATX administration. The same pattern of results with guanfacine suggests that the effects of increased NE are due in part to binding at α-2 noradrenergic receptors.


Norepinephrine α-2 noradrenergic receptors Atomoxetine Guanfacine Rat Lapses of attention Distribution skew Reaction time variability ADHD Distractors 



The department of Psychology at the University of Mississippi provided funding for this project.

Compliance with ethical standards

All procedures using animals were approved by the University of Mississippi Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Arnsten AFT, Cai JX, Goldman-Rakic PS (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8:4287–4298PubMedPubMedCentralCrossRefGoogle Scholar
  2. Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450PubMedPubMedCentralCrossRefGoogle Scholar
  3. Baarendse PJJ, Vanderschuren LJMJ (2012) Dissociable effects of monoamine reuptake inhibitors on distinct forms of impulsive behavior in rats. Psychopharmacology 219:313–326PubMedCrossRefGoogle Scholar
  4. Barkley RA (2006) Attention-deficit hyperactivity disorder: a handbook for diagnosis and treatment, 3rd edn. Guilford Press, New YorkGoogle Scholar
  5. Bédard AV, Stein MA, Halperin JM, Krone B, Rajwan E, Newcorn JH (2015) Differential impact of methylphenidate and atomoxetine on sustained attention in youth with attention-deficit/hyperactivity disorder. J Child Psychol Psychiatry 56:40–48PubMedCrossRefGoogle Scholar
  6. Benn A, Robinson ESJ (2017) Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat. Psychopharmacology 234:255–266PubMedCrossRefGoogle Scholar
  7. Bidwell LC, Dew RE, Kollins SH (2010) Alpha-2 adrenergic receptors and attention-deficit/hyperactivity disorder. Curr Psychiatry Rep 12:366–373PubMedCentralCrossRefPubMedGoogle Scholar
  8. Blondeau C, Dellu-Hagedorn F (2007) Dimensional analysis of ADHD subtypes in rats. Biol Psychiatry 61:1340–1350PubMedCrossRefGoogle Scholar
  9. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular level of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711PubMedCrossRefGoogle Scholar
  10. Caballero-Puntiverio M, Lerdrup LS, Grupe M, Larsen CW, Dietz AG, Andreasen JT (2019) Effect of ADHD medication in male C57BL/6J mice performing the rodent continuous performance test. Psychopharmacology:1–13Google Scholar
  11. Chamberlain SR, del Campo N, Dowson J, Müller U, Clark L, Robbins TW, Sahakian BJ (2007) Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biol Psychiatry 62:977–984PubMedCrossRefGoogle Scholar
  12. Corbetta M, Shulman GL (2002) Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci 3:201–215PubMedCrossRefGoogle Scholar
  13. Decamp E, Clark K, Schneider JS (2011) Effects of the alpha-2 adrenoceptor agonist guanfacine on attention and working memory in aged non-human primates. Eur J Neurosci 34:1018–1022PubMedPubMedCentralCrossRefGoogle Scholar
  14. Ding Z, Brown JW, Rueter LE, Mohler EG (2018) Profiling attention and cognition enhancing drugs in a rat touchscreen-based continuous performance test. Psychopharmacology 235:1093–1105PubMedCrossRefGoogle Scholar
  15. Durstewitz D, Seamans JK, Sejnowski TJ (2000) Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol 83:1733–1750PubMedCrossRefGoogle Scholar
  16. Fan LY, Chou TL, Gau SSF (2017) Neural correlates of atomoxetine improving inhibitory control and visual processing in drug-naïve adults with attention-deficit/hyperactivity disorder. Hum Brain Mapp 38:4850–4864PubMedCrossRefGoogle Scholar
  17. Fernando ABP, Economidou D, Theobald DE, Zou M, Newman AH, Spoelder M, Caprioli D, Moreno M, Hipólito L, Aspinall AT, Robbins TW, Dalley JW (2012) Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists. Psychopharmacology 219:341–352PubMedCrossRefGoogle Scholar
  18. Gau SSF, Shang CY (2010) Improvement of executive functions in boys with attention deficit hyperactivity disorder: an open-label follow-up study with once-daily atomoxetine. Int J Neuropsychopharmacol 13:243–256PubMedCrossRefGoogle Scholar
  19. Geyer MA, Segal DS, Mandell AJ (1972) Effect of intraventricular infusion of dopamine and norepinephrine on motor activity. Physiol Behav 8:653–658PubMedCrossRefGoogle Scholar
  20. Hauser J, Reissmann A, Sontag TA, Tucha O, Lange KW (2017) Effects of atomoxetine on attention in Wistar rats treated with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). ADHD Atten Deficit Hyperact Disord 9:253–262CrossRefGoogle Scholar
  21. Hausknecht KA, Acheson A, Farrar AM, Kieres AK, Shen R, Richards JB, Sabol KE (2005) Prenatal alcohol exposure causes attention deficits in male rats. Behav Neurosci 119:302–310PubMedCrossRefGoogle Scholar
  22. Heil SH, Holmes HW, Bickel WK, Higgins ST, Badger GJ, Laws HF, Faries DE (2002) Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend 67:149–156PubMedCrossRefGoogle Scholar
  23. Hohle RH (1967) Component process latencies in reaction times of children and adults. Adv Child Dev Behav 3:225–261CrossRefGoogle Scholar
  24. Jäkälä P, Riekkinen M, Sirviö J, Koivisto E, Riekkinen P (1999) Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers. Neuropsychopharmacology 21:495–502PubMedCrossRefGoogle Scholar
  25. Jarrott B, Louis WJ, Summers RJ (1982) [3H]-guanfacine: a radioligand that selectively labels high affinity α2-adrenoceptor sites in homogenates of rat brain. Br J Pharmacol 75:401–408PubMedPubMedCentralCrossRefGoogle Scholar
  26. Jentsch JD, Aarde SM, Seu E (2008) Effects of atomoxetine and methylphenidate on performance of a lateralized reaction time task in rats. Psychopharmacology 202:497–504PubMedCrossRefGoogle Scholar
  27. Jones BE, Moore RY (1977) Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res 127:23–53CrossRefGoogle Scholar
  28. Koffarnus MN, Katz JL (2011) Response requirement and increases in accuracy produced by stimulant drugs in a 5-choice serial reaction-time task in rats. Psychopharmacology 213:723–733PubMedCrossRefGoogle Scholar
  29. Kofler MJ, Rapport MD, Sarver DE, Raiker J, Orban S, Friedman L, Kolomeyer E (2013) Reaction time variability in ADHD: a meta-analytic review of 319 studies. Clin Psychol Rev 33:795–811PubMedCrossRefGoogle Scholar
  30. Kratochvil CJ, Heiligenstein JH, Dittmann R, Spencer TJ, Biederman J, Wernicke J, Newcorn JH, Casat C, Milton D, Michelson D (2002) Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry 41:776–784PubMedCrossRefGoogle Scholar
  31. Kratz O, Studer P, Baack J, Malcherek S, Erbe K, Moll GH, Heinrich H (2012) Differential effects of methylphenidate and atomoxetine on attentional processes in children with ADHD: an event-related potential study using the Attention Network Test. Prog Neuro-Psychopharmacol Biol Psychiatry 37:81–89CrossRefGoogle Scholar
  32. Langner R, Eickhoff SB (2013) Sustaining attention to simple tasks: a meta-analytic review of the neural mechanisms of vigilant attention. Psychol Bull 139:870–900PubMedCrossRefGoogle Scholar
  33. Leth-Steensen C, King Elbaz Z, Douglas VI (2000) Mean response times, variability, and skew in the responding of ADHD children: a response time distributional approach. Acta Psychol 104:167–190CrossRefGoogle Scholar
  34. Lin HY, Gau SSF (2016) Atomoxetine treatment strengthens an anti-correlated relationship between functional brain networks in medication-naïve adults with attention-deficit hyperactivity disorder: a randomized double-blind placebo-controlled clinical trial. Int J Neuropsychopharmacol 19:1–15CrossRefGoogle Scholar
  35. Liu YP, Huang TS, Tung CS, Lin CC (2015) Effects of atomoxetine on attention and impulsivity in the five-choice serial reaction time task in rats with lesions of dorsal noradrenergic ascending bundle. Prog Neuro-Psychopharmacol Biol Psychiatry 56:81–90CrossRefGoogle Scholar
  36. Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D (2003) Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 53:112–120PubMedCrossRefGoogle Scholar
  37. Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, Newcorn J, Sallee FR, Sangal RB, Saylor K, West S, Kelsey D, Wernicke J, Trapp NJ, Harder D (2002) Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 159:1896–1901PubMedCrossRefGoogle Scholar
  38. Milstein JA, Lehmann O, Theobald DEH, Dalley JW, Robbins TW (2007) Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase–saporin impairs attentional function and enhances the effects of guanfacine in the rat. Psychopharmacology 190:51–63PubMedCrossRefGoogle Scholar
  39. Nandam LS, Hester R, Wagner J, Cummins TDR, Garner K, Dean AJ, Kim BN, Nathan PJ, Mattingley JB, Bellgrove MA (2011) Methylphenidate but not atomoxetine or citalopram modulates inhibitory control and response time variability. Biol Psychiatry 69:902–904PubMedCrossRefGoogle Scholar
  40. Navarra R, Graf R, Huang Y, Logue S, Comery T, Hughes Z, Day M (2008) Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test. Prog Neuro-Psychopharmacol Biol Psychiatry 32:34–41CrossRefGoogle Scholar
  41. Ni HC, Hwang Gu SL, Lin HY, Lin YJ, Yang LK, Huang HC, Gau SSF (2016) Atomoxetine could improve intra-individual variability in drug-naïve adults with attention-deficit/hyperactivity disorder comparably with methylphenidate: a head-to-head randomized clinical trial. J Psychopharmacol (Oxf) 30:459–467CrossRefGoogle Scholar
  42. Ni HC, Shang CY, Gau SSF, Lin YJ, Huang HC, Yang LK (2013) A head-to-head randomized clinical trial of methylphenidate and atomoxetine treatment for executive function in adults with attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol 16:1959–1973PubMedCrossRefGoogle Scholar
  43. Paterson NE, Ricciardi J, Wetzler C, Hanania T (2011) Sub-optimal performance in the 5-choice serial reaction time task in rats was sensitive to methylphenidate, atomoxetine and d-amphetamine, but unaffected by the COMT inhibitor tolcapone. Neurosci Res 69:41–50PubMedCrossRefGoogle Scholar
  44. Paterson NE, Wetzler C, Hackett A, Hanania T (2012) Impulsive action and impulsive choice are mediated by distinct neuropharmacological substrates in rat. Int J Neuropsychopharmacol 15:1473–1487PubMedCrossRefGoogle Scholar
  45. Petersen SE, Posner MI (2012) The attention system of the human brain: 20 years after. Annu Rev Neurosci 35:73–89PubMedPubMedCentralCrossRefGoogle Scholar
  46. Pillidge K, Porter AJ, Dudley JA, Tsai YC, Heal DJ, Stanford SC (2014) The behavioural response of mice lacking NK1 receptors to guanfacine resembles its clinical profile in treatment of ADHD. Br J Pharmacol 171:4785–4796PubMedPubMedCentralCrossRefGoogle Scholar
  47. Posey DJ, Wiegand RE, Wilkerson J, Maynard M, Stigler KA, McDougle CJ (2006) Open-label atomoxetine for attention-deficit/ hyperactivity disorder symptoms associated with high-functioning pervasive developmental disorders. J Child Adolesc Psychopharmacol 16:599–610PubMedCrossRefGoogle Scholar
  48. Richards J, Gancarz A, Hawk, Jr. L (2011) Animal models of behavioral processes that underlie the occurrence of impulsive behaviors in humans. In: Inhibitory control and drug abuse prevention: from research to translation. Springer Science & Business Media, pp 13–41Google Scholar
  49. Robbins T (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380PubMedCrossRefGoogle Scholar
  50. Robinson ESJ (2012) Blockade of noradrenaline re-uptake sites improves accuracy and impulse control in rats performing a five-choice serial reaction time tasks. Psychopharmacology 219:303–312PubMedCrossRefGoogle Scholar
  51. Robinson ESJ, Eagle DM, Mar AC, Banerjee G (2008) Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology 33:1028–1037PubMedPubMedCentralCrossRefGoogle Scholar
  52. Ruggiero S, Clavenna A, Reale L, Capuano A, Rossi F, Bonati M (2014) Guanfacine for attention deficit and hyperactivity disorder in pediatrics: a systematic review and meta-analysis. Eur Neuropsychopharmacol 24:1578–1590PubMedCrossRefGoogle Scholar
  53. Sabol KE, Richards JB, Broom SL, Roach JT, Hausknecht K (2003) Effects of stimulus salience and methamphetamine on choice reaction time in the rat: central tendency versus distribution skew. Behav Pharmacol 14:489–500PubMedCrossRefGoogle Scholar
  54. Sagvolden T (2006) The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of attention-deficit/hyperactivity disorder (ADHD). Behav Brain Funct 2:41PubMedPubMedCentralCrossRefGoogle Scholar
  55. Sallee FR, Kollins SH, Wigal TL (2012) Efficacy of guanfacine extended release in the treatment of combined and inattentive only subtypes of attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 22:206–214PubMedPubMedCentralCrossRefGoogle Scholar
  56. Sallee FR, Mcgough J, Wigal T, Donahue J, Lyne A, Biederman J, SPD503 Study Group (2009) Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 48:155–165PubMedCrossRefGoogle Scholar
  57. Scahill L, Chappell P, Kim Y, Schultz RT, Katsovich L, Shepherd E, Arnsten AFT, Cohen DJ, Leckman JF (2001) A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry 158:1067–1074PubMedCrossRefGoogle Scholar
  58. Shang CY, Gau SSF (2012) Improving visual memory, attention, and school function with atomoxetine in boys with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 22:353–363PubMedCrossRefGoogle Scholar
  59. Sun H, Cocker PJ, Zeeb FD, Winstanley CA (2012) 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 219:285–301PubMedCrossRefGoogle Scholar
  60. Tamm L, Narad ME, Antonini TN, O'Brien KM, Hawk LW, Epstein JN (2012) Reaction time variability in ADHD: a review. Neurotherapeutics 9:500–508PubMedPubMedCentralCrossRefGoogle Scholar
  61. Timmermans PBMWM, Schoop AMC, Van Zwieten PA (1982) Binding characteristics of [3H] guanfacine to rat brain α-adrenoceptors: comparison with [3H]clonidine. Biochem Pharmacol 31:899–905PubMedCrossRefGoogle Scholar
  62. Tomlinson A, Grayson B, Marsh S, Harte MK, Barnes SA, Marshall KM, Neill JC (2014) Pay attention to impulsivity: modelling low attentive and high impulsive subtypes of adult ADHD in the 5-choice continuous performance task (5C-CPT) in female rats. Eur Neuropsychopharmacol 24:1371–1380PubMedCrossRefGoogle Scholar
  63. Tsutsui-Kimura I, Ohmura Y, Izumi T, Yamaguchi T, Yoshida T, Yoshioka M (2009) The effects of serotionin and/or noradrenaline reuptake inhibitors on impulsive-like action assessed by the three-choice serial reaction time task: a simple and valid model of impulsive action using rats. Behav Pharmacol 20:474–483PubMedCrossRefGoogle Scholar
  64. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AFT (2007) α2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410PubMedCrossRefGoogle Scholar
  65. Wehmeier PM, Schacht A, Ulberstad F, Lehmann M, Schneider-Fresenius C, Lehmkuhl G, Dittmann RW, Banaschewski T (2012) Does atomoxetine improve executive function, inhibitory control, and hyperactivity?: results from a placebo-controlled trial using quantitative measurement technology. J Clin Psychopharmacol 32:653–660PubMedCrossRefGoogle Scholar
  66. Wehmeier PM, Schacht A, Wolff C, Otto WR, Dittmann RW, Banaschewski T (2011) Neuropsychological outcomes across the day in children with attention-deficit/hyperactivity disorder treated with atomoxetine: results from a placebo-controlled study using a computer-based continuous performance test combined with an infra-red motion-tracking device. J Child Adolesc Psychopharmacol 21:433–444PubMedCrossRefGoogle Scholar
  67. Wilens TE, Robertson B, Sikirica V, Harper L, Young JL, Bloomfield R, Lyne A, Rynkowski G, Cutler AJ (2015) A randomized, placebo-controlled trial of guanfacine extended release in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 54:916–925PubMedCrossRefGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychologyThe University of MississippiUniversityUSA
  2. 2.Virginia Commonwealth University Health SystemRichmondUSA

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