Psychopharmacology

, Volume 231, Issue 13, pp 2671–2679 | Cite as

Atomoxetine reduces anticipatory responding in a 5-choice serial reaction time task for adult zebrafish

  • Matthew O. Parker
  • Alistair J. Brock
  • Ari Sudwarts
  • Caroline H. Brennan
Original Investigation

Abstract

Deficits in impulse control are related to a number of psychiatric diagnoses, including attention deficit hyperactivity disorder, addiction, and pathological gambling. Despite increases in our knowledge about the underlying neurochemical and neuroanatomical correlates, understanding of the molecular and cellular mechanisms is less well established. Understanding these mechanisms is essential in order to move towards individualized treatment programs and increase efficacy of interventions. Zebrafish are a very useful vertebrate model for exploring molecular processes underlying disease owing to their small size and genetic tractability. Their utility in terms of behavioral neuroscience, however, hinges on the validation and publication of reliable assays with adequate translational relevance. Here, we report an initial pharmacological validation of a fully automated zebrafish version of the commonly used five-choice serial reaction time task using a variable interval pre-stimulus interval. We found that atomoxetine reduced anticipatory responses (0.6 mg/kg), whereas a high-dose (4 mg/kg) methylphenidate increased anticipatory responses and the number of trials completed in a session. On the basis of these results, we argue that similar neurochemical processes in fish as in mammals may control impulsivity, as operationally defined by anticipatory responses on a continuous performance task such as this, making zebrafish potentially a good model for exploring the molecular basis of impulse control disorders and for first-round drug screening.

Keywords

Five-choice serial reaction time task Zebrafish Impulsivity Addiction ADHD Atomoxetine Methylphenidate 

Notes

Acknowledgments

This research was funded by project grant G1000053 from the National Center for the Replacement, Reduction and Refinement of animals in research (NC3Rs; UK) and by the Medical Research Council (MRC; UK). CHB is a Royal Society (UK) Industrial Research Fellow. We acknowledge the contributions of Dennis Ife, Jun Ma and Chris Straw of the School of Engineering and Materials Science at Queen Mary University of London for building and engineering the automated testing arena, and Dr Fabrizio Smeraldi (Electronic Engineering and Computer Science) and Mahesh Pancholi (School of Biological and Chemical Sciences) for writing the visual tracking programming. We also thank the two anonymous reviewers for their helpful and constructive comments on earlier versions of this manuscript.

References

  1. Alessi S, Petry N (2003) Pathological gambling severity is associated with impulsivity in a delay discounting procedure. Behav Process 64:345–354CrossRefGoogle Scholar
  2. Amsterdam A, Burgess S, Golling G, Chen W, Sun Z, Townsend K, Farrington S, Haldi M, Hopkins N (1999) A large-scale insertional mutagenesis screen in zebrafish. Genes Dev 13:2713–2724PubMedCentralPubMedCrossRefGoogle Scholar
  3. Amsterdam A, Nissen RM, Sun Z, Swindell EC, Farrington S, Hopkins N (2004) Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci U S A 101:12792–12797PubMedCentralPubMedCrossRefGoogle Scholar
  4. Bari A, Dalley JW, Robbins TW (2008) The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc 3:759–767PubMedCrossRefGoogle Scholar
  5. Barkley RA (1997) Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 121:65PubMedCrossRefGoogle Scholar
  6. Behrend ER, Domesick VB, Bitterman M (1965) Habit reversal in the fish. J Comp Physiol Psychol 60:407PubMedCrossRefGoogle Scholar
  7. Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ (2008) High impulsivity predicts the switch to compulsive cocaine-taking. Science 320:1352–1355PubMedCentralPubMedCrossRefGoogle Scholar
  8. Bitterman M (1965) Phyletic differences in learning. Am Psychol 20:396PubMedCrossRefGoogle Scholar
  9. Bitterman M, Mackintosh N (1969) Habit reversal and probability learning: rats, birds, and fish. Animal Discrimination Learning. 163–185Google Scholar
  10. Bizarro L, Patel S, Murtagh C, Stolerman I (2004) Differential effects of psychomotor stimulants on attentional performance in rats: nicotine, amphetamine, caffeine and methylphenidate. Behav Pharmacol 15:195–206PubMedGoogle Scholar
  11. Bymaster F, Katner J, Nelson D, Hemrick-Luecke S, Threlkeld P, Heiligenstein J, Morin S, Gehlert D, Perry K (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711PubMedCrossRefGoogle Scholar
  12. Caprioli D, Sawiak SJ, Merlo E, Theobald DE, Spoelder M, Jupp B, Voon V, Carpenter TA, Everitt BJ, Robbins TW (2013) Gamma aminobutyric acidergic and neuronal structural markers in the nucleus accumbens core underlie trait-like impulsive behavior. Biol PsychiatryGoogle Scholar
  13. Carli M, Robbins T, Evenden J, Everitt B (1983) Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380PubMedCrossRefGoogle Scholar
  14. 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
  15. Cole B, Robbins T (1987) Amphetamine impairs the discrimination performance of rats with dorsal bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions. Psychopharmacology 91:458–466PubMedCrossRefGoogle Scholar
  16. Cole B, Robbins T (1989) Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: implications for theories of selective attention and arousal. Behav Brain Res 33:165–179PubMedCrossRefGoogle Scholar
  17. Dalley JW, Roiser JP (2012) Dopamine, serotonin and impulsivity. NeuroscienceGoogle Scholar
  18. Dalley J, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity, and top–down cognitive control. Neuron 69:680–694PubMedCrossRefGoogle Scholar
  19. Darland T, Dowling JE (2001) Behavioral screening for cocaine sensitivity in mutagenized zebrafish. Proc Natl Acad Sci U S A 98:11691–11696PubMedCentralPubMedCrossRefGoogle Scholar
  20. Economidou D, Pelloux Y, Robbins TW, Dalley JW, Everitt BJ (2009) High impulsivity predicts relapse to cocaine-seeking after punishment-induced abstinence. Biol Psychiatry 65:851–856PubMedCrossRefGoogle Scholar
  21. Economidou D, Dalley JW, Everitt BJ (2011) Selective norepinephrine reuptake inhibition by atomoxetine prevents cue-induced heroin and cocaine seeking. Biol Psychiatry 69:266–274PubMedCrossRefGoogle Scholar
  22. Economidou D, Theobald DE, Robbins TW, Everitt BJ, Dalley JW (2012) Norepinephrine and Dopamine Modulate Impulsivity on the Five-Choice Serial Reaction Time Task Through Opponent Actions in the Shell and Core Sub-Regions of the Nucleus Accumbens. NeuropsychopharmacologyGoogle Scholar
  23. Everitt BJ, Belin D, Economidou D, Pelloux Y, Dalley JW, Robbins TW (2008) Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Phil Trans R Soc London B Biol Sci 363:3125–3135CrossRefGoogle Scholar
  24. Fernando AB, Economidou D, Theobald DE, Zou MF, Newman AH, Spoelder M, Caprioli D, Moreno M, Hipolito 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 219:341–352PubMedCentralPubMedCrossRefGoogle Scholar
  25. Golling G, Amsterdam A, Sun Z, Antonelli M, Maldonado E, Chen W, Burgess S, Haldi M, Artzt K, Farrington S (2002) Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development. Nat Genet 31:135–140PubMedCrossRefGoogle Scholar
  26. Guo S (2004) Linking genes to brain, behavior and neurological diseases: what can we learn from zebrafish? Genes Brain Behav 3:63–74PubMedCrossRefGoogle Scholar
  27. Guo S, Wilson SW, Cooke S, Chitnis AB, Driever W, Rosenthal A (1999) Mutations in the zebrafish unmask shared regulatory pathways controlling the development of catecholaminergic neurons. Dev Biol 208:473–487PubMedCrossRefGoogle Scholar
  28. Holzschuh J, Ryu S, Aberger F, Driever W (2001) Dopamine transporter expression distinguishes dopaminergic neurons from other catecholaminergic neurons in the developing zebrafish embryo. Mech Dev 101:237–243PubMedCrossRefGoogle Scholar
  29. Hosking J, Winstanley C (2011) Impulsivity as a mediating mechanism between early-life adversity and addiction: theoretical comment on Lovic et al. Behav Neurosci 125:681–686PubMedCrossRefGoogle Scholar
  30. Korf J, Aghajanian G, Roth R (1973) Increased turnover of norepinephrine in the rat cerebral cortex during stress: role of the locus coeruleus. Neuropharmacology 12:933–938PubMedCrossRefGoogle Scholar
  31. Lange M, Norton W, Coolen M, Chaminade M, Merker S, Proft F, Schmitt A, Vernier P, Lesch K, Bally-Cuif L (2012) The ADHD-susceptibility gene lphn3. 1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development. Mol Psychiatry 17:946–954PubMedCrossRefGoogle Scholar
  32. Ma PM (1997) Catecholaminergic systems in the zebrafish. III. Organization and projection pattern of medullary dopaminergic and noradrenergic neurons. J Comp Neurol 381:411–427PubMedCrossRefGoogle Scholar
  33. Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, Spencer T (2001) Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose–response study. Pediatrics 108:e83–e83PubMedCrossRefGoogle Scholar
  34. Milstein JA, Dalley JW, Robbins TW (2010) Methylphenidate-induced impulsivity: pharmacological antagonism by beta-adrenoreceptor blockade. J Psychopharmacol 24:309–321PubMedCrossRefGoogle Scholar
  35. Muto A, Orger MB, Wehman AM, Smear MC, Kay JN, Page-McCaw PS, Gahtan E, Xiao T, Nevin LM, Gosse NJ (2005) Forward genetic analysis of visual behavior in zebrafish. PLoS Genet 1:e66PubMedCentralPubMedCrossRefGoogle Scholar
  36. 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
  37. Parker M, Brennan C (2012) Zebrafish (Danio rerio) models of substance abuse: harnessing the capabilities. Behaviour 149:10–12CrossRefGoogle Scholar
  38. Parker M, Millington M, Combe F, Brennan C (2012a) Development and implementation of a three-choice serial reaction time task for zebrafish (Danio rerio). Behav Brain Res 227:73–80PubMedCrossRefGoogle Scholar
  39. Parker MO, Gaviria J, Haigh A, Millington ME, Brown VJ, Combe FJ, Brennan CH (2012b) Discrimination reversal and attentional sets in zebrafish (Danio rerio). Behav Brain Res 232:264–268PubMedCrossRefGoogle Scholar
  40. Parker M, Brock A, Walton R, Brennan C (2013a) The role of zebrafish (Danio rerio) in dissecting the genetics and neural circuits of executive function. Front Neural Circ 7:63Google Scholar
  41. Parker M, Ife D, Ma J, Pancholi M, Smeraldi F, Straw C, Brennan C (2013b) Development and automation of a test of impulse control in zebrafish. Front Syst Neurosci 7:65PubMedCentralPubMedCrossRefGoogle Scholar
  42. Pliszka S, McCracken J, Maas J (1996) Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry 35:264–272PubMedCrossRefGoogle Scholar
  43. Rink E, Guo S (2004) The too few mutant selectively affects subgroups of monoaminergic neurons in the zebrafish forebrain. Neuroscience 127:147–154PubMedCrossRefGoogle Scholar
  44. Rink E, Wullimann MF (2001) The teleostean (zebrafish) dopaminergic system ascending to the subpallium (striatum) is located in the basal diencephalon (posterior tuberculum). Brain Res 889:316–330PubMedCrossRefGoogle Scholar
  45. Rink E, Wullimann MF (2002) Development of the catecholaminergic system in the early zebrafish brain: an immunohistochemical study. Dev Brain Res 137:89–100CrossRefGoogle Scholar
  46. Robbins T (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380PubMedCrossRefGoogle Scholar
  47. Robinson ES, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X, Dalley JW, Robbins TW (2008) Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology 33:1028–1037PubMedCrossRefGoogle Scholar
  48. Tay T, Ronneberger O, Ryu S, Nitschke R, Driever W (2011) Comprehensive catecholaminergic projectome analysis reveals single-neuron integration of zebrafish ascending and descending dopaminergic systems. Nat Commun 2:171PubMedCentralPubMedCrossRefGoogle Scholar
  49. Urcelay G, Dalley J (2012) Linking ADHD, impulsivity, and drug abuse: a neuropsychological perspective. Curr Top Behav Neurosci 9:173–197PubMedCrossRefGoogle Scholar
  50. Westerfield M (1993) The zebrafish book: a guide for the laboratory use of zebrafish (Brachydanio rerio). M. Westerfield Eugene, ORGoogle Scholar
  51. Winstanley C, Eagle D, Robbins T (2006) Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clin Psychol Rev 26:379–395PubMedCentralPubMedCrossRefGoogle Scholar
  52. Woodward WT, Schoel WM, Bitterman ME (1971) Reversal learning with singly presented stimuli in pigeons and goldfish. J Comp physiol Psychol 76:460–467PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Matthew O. Parker
    • 1
  • Alistair J. Brock
    • 1
  • Ari Sudwarts
    • 1
  • Caroline H. Brennan
    • 1
  1. 1.Zebrafish Neurobiology and Behavioural Genetics Research Group, School of Biological and Chemical SciencesQueen Mary University of LondonLondonUK

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