Abstract
Rationale
A novel rodent continuous performance test (CPT) was developed as one of the goals of the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium to improve its translatability to the CPT test used in human subjects.
Objectives
The objective of the study is to investigate the effects of attention and cognition enhancing drugs in rodent CPT.
Methods
A single cohort of rats were trained to asymptotic performance in the test. Pharmacological test sessions were then performed twice per week in a full crossover design with the following drugs tested: methylphenidate (0.3, 1, and 3 mg/kg), the α4β2 nicotinic agonist ABT-594 (0.0023, 0.007 and 0.023 mg/kg), modafinil (8, 16, and 32 mg/kg), atomoxetine (0.3, 1, and 3 mg/kg), donepezil (0.1, 0.3, and 1 mg/kg), and memantine (1.25, 2.5, and 5 mg/kg).
Results
The stimulant-like drugs methylphenidate, ABT-594, and modafinil were found to increase measures of impulsivity and overall responding with generally no positive effects on d’, a putative measure of attention, with the exception of ABT-594 which improved d’ at the highest dose tested. Atomoxetine and the memory-enhancing drugs donepezil and memantine, on the other hand, were found to reduce measures of impulsivity and responding and had either negligible or worsening effects on d’.
Conclusions
Our results suggest rodent CPT can detect changes in impulsivity resulting from drugs known to improve attention in rodents and humans. However, additional work is needed to assess the sensitivity and validity of this assay for assessing effects on attention.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bain EE, Robieson W, Pritchett Y, Garimella T, Abi-Saab W, Apostol G, McGough JJ, Saltarelli MD (2013) A randomized, double-blind, placebo-controlled phase 2 study of α4β2 agonist ABT-894 in adults with ADHD. Neuropsychopharmacology 38(3):405–413. https://doi.org/10.1038/npp.2012.194
Benn A, Robinson ES (2014) Investigating glutamatergic mechanism in attention and impulse control using rats in a modified 5-choice serial reaction time task. PLoS One 9(12):1–22
Bracco L, Bessi V, Padiglioni S, Marini S, Pepeu G (2014) Do cholinesterase inhibitors act primarily on attention deficit? A naturalistic study in Alzheimer’s disease patients. J Alzheimers Dis 40(3):737–742. https://doi.org/10.3233/JAD-131154
Callahan PM, Terry AV Jr (2015) Attention. Cognitive enhancement. In: Kantak KM, Wettstein JG (eds) Handbook of experimental pharmacology. Springer, New York
Chamberlain SR, Müller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ (2006) Neurochemical modulation of response inhibition and probabilistic learning in humans. Science 311(5762):861–863. https://doi.org/10.1126/science.1121218
Chuah LYM, Chee MWL (2008) Cholinergic augmentation modulates visual task performance in sleep-deprived young adults. J Neurosci 28(44):11369–11377. https://doi.org/10.1523/JNEUROSCI.4045-08.2008
Dean AC, Sevak RJ, Monterosso JR, Hellemann G, Sugar CA, London ED (2011) Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans. J Stud Alcohol Drugs 72(6):943–953. https://doi.org/10.15288/jsad.2011.72.943
Eagle DM, Baunez C (2010) Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition. Neurosci Biobehav Rev 34(1):50–72. https://doi.org/10.1016/j.neubiorev.2009.07.003
Eagle DM, Tufft MR, Goodchild HL, Robbins TW (2007) Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol. Psychopharmacology 192(2):193–206. https://doi.org/10.1007/s00213-007-0701-7
Green DM, Swets JA (1966) Signal detection theory and psychophysics. Wiley & Sons, New York
Kim CH, Hvoslef-Eide M, Nilsson SRO, Johnson MR, Herbert BR, Robbins TW, Saksida LM, Bussey TJ, Mar AC (2015) The continuous performance test (rCPT) for mice: a novel operant touchscreen test of attentional function. Psychopharmacology 232(21–22):3947–3966. https://doi.org/10.1007/s00213-015-4081-0
Mar AC, Horner AE, Nilsson SR, Alsio J, Kenth BA et al (2013) The touschscreen platform for assessing executive function in rats and mice. Nat Protoc 8(10):1985–2005. https://doi.org/10.1038/nprot.2013.123
McGaughy J, Sarter M (1998) Sustained attention performance in rats with intracortical infusions of 192 lgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142. Behav Neurosci 112(6):1519–1525. https://doi.org/10.1037/0735-7044.112.6.1519
Min SK, Moon IW, Rw K, Hs S (2001) Effects of transdermal nicotine on attention and memory in healthy elderly non-smokers. Psychopharmacology 159(1):83–88. https://doi.org/10.1007/s002130100899
Mirza N, Stolerman IP (2000) The role of nicotinic and muscarinic acetylcholine receptors in attention. Psychopharmacology 107:541–550
Mohler EG, Franklin SR, Rueter LE, Fox GB, Decker MW, Browman KE (2010) ABT-594 improves performance in the 5-choice serial reaction time task under conditions of increased difficulty, sub-chronic dosing, and in poorly-performing subjects. Pharmacol Biochem Behav 95(2):146–157. https://doi.org/10.1016/j.pbb.2009.12.019
Morgan RE, Crowley JM, Smith RH, LaRoche RB, Dopheide MM (2007) Modafinil improves attention, inhibitory control, and reaction time in healthy, middle-aged rats. Pharmacol Biochem Behav 86(3):531–541. https://doi.org/10.1016/j.pbb.2007.01.015
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(1):34–41. https://doi.org/10.1016/j.pnpbp.2007.06.017
Parasuraman R (1979) Memory load and event rate control sensitivity decrements in sustained attention. Science 205(4409):924–927. https://doi.org/10.1126/science.472714
Rammsayer TH (2006) Effects of pharmacologically induced changes in NMDA receptor activity on human timing and sensorimotor performance. Brain Res 1073–1074:407–416
Repantis D, Laisney O, Heuser I (2010a) Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res 61(6):473–481. https://doi.org/10.1016/j.phrs.2010.02.009
Repantis D, Schlattmann P, Laisney O, Heuser I (2010b) Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res 62(3):187–206. https://doi.org/10.1016/j.phrs.2010.04.002
Rezvani AH, Cauley MC, Johnson EC, Gatto GJ, Levin ED (2012) Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats. Psychopharmacology 223(3):251–258. https://doi.org/10.1007/s00213-012-2712-2
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(2):303–312. https://doi.org/10.1007/s00213-011-2420-3
Rokem A, Landau AN, Garg D, Prinzmetal W, Silver MA (2010) Cholinergic enhancement increases the effects of voluntary attention but does not affect involuntary attention. Neuropsychopharmacology 35(13):2538–2544. https://doi.org/10.1038/npp.2010.118
Romberg C, Mattson MP, Murgai MR, Bussey TJ, Saksida LM (2011) Impaired attention in mice in the 3XTgAD mouse model of Alzheimer’s disease: rescue by donepezil (Aricept). J Neurosci 31(9):3500–3507. https://doi.org/10.1523/JNEUROSCI.5242-10.2011
Rosvold HE, Mirsky AF, Sarason I, Bransome EDJ, Beck LH (1956) A continuous performance test of brain damage. J Consult Psychol 20(5):343–350. https://doi.org/10.1037/h0043220
Sahakian B, Jones G, Levy R, Gray J, Warburton D (1989) The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br J Psychiatry 154(6):797–800. https://doi.org/10.1192/bjp.154.6.797
Sahakian BJ, Bruhl AB, Cook J, Killikelly C, Savulich G, Piercy T, Hafizi S, Perez J, Fernandez-Egea E, Suckling J, Jones PB (2015) The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people. Philos Trans R Soc Lond Ser B Biol Sci 370(1677):20140214. https://doi.org/10.1098/rstb.2014.0214
Schmaal L, Joos L, Koeleman M, Veltman DJ, van den Brink W, Goudriaan AE (2013) Effects of modafinil on neural correlates of response inhibition in alcohol-dependent patients. Biol Psychiatry 73(3):211–218. https://doi.org/10.1016/j.biopsych.2012.06.032
Scoriels L, Barnett JH, Soma PK, Sahakian BJ, Jones PB (2012) Effects of modafinil on cognitive functions in first episode psychosis. Psychopharmacology 220(2):249–258. https://doi.org/10.1007/s00213-011-2472-4
Smith JW, Gastambide F, Gilmour G, Dix S, Foss J, Lloyd K, Malik N, Tricklebank M (2011) A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory. Psychopharmacology 217(2):255–269. https://doi.org/10.1007/s00213-011-2277-5
Tomlinson A, Grayson B, Marsh S, Hayward A, Marshall KM, Neill JC (2015) Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model. Eur Neuropsychopharmacol 25(4):454–467. https://doi.org/10.1016/j.euroneuro.2014.11.016
Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003) Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology 165(3):260–269. https://doi.org/10.1007/s00213-002-1250-8
Turner DC, Clark L, Dowson J, Robbins TW, Sahakian BJ (2004) Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 55(10):1031–1040. https://doi.org/10.1016/j.biopsych.2004.02.008
Waters KA, Burnham KE, O'connor D, Dawson GR, Dias R (2005) Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat. J Psychopharmacol 19(2):149–158. https://doi.org/10.1177/0269881105048995
Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ (2002) Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 59:238–247
Wesnes KA, Aarsland D, Ballard C, Londos E (2015) Memantine improves attention and episodic memory in Parkinson’s disease dementia and dementia with Lewy bodies. Int J Geriatr Psychiatry 30(1):46–54. https://doi.org/10.1002/gps.4109
White HK, Levin ED (1999) Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology 143(2):158–165. https://doi.org/10.1007/s002130050931
Young JW, Light GA, Marston HM et al (2009) The 5-choice continuous performance test: evidence for a translational test of vigilance for mice. PLoS One 4(1):1–22
Acknowledgements
AbbVie was responsible for the study design, research, analysis, data collection, interpretation of data, and writing, reviewing, and approving of the publication. All authors are current or past employees of AbbVie and may own AbbVie stock.
This work was funded by AbbVie and received support from the NEWMEDS Innovative Medicine Initiative Joint Undertaking grant 115008, composed of EFPIA in-kind contribution and financial contribution from the EU’s 7th Framework Program (FP7/2007-2013).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Supplemental Table 1
(XLSX 12 kb)
Rights and permissions
About this article
Cite this article
Ding, Z., Brown, J.W., Rueter, L.E. et al. Profiling attention and cognition enhancing drugs in a rat touchscreen-based continuous performance test. Psychopharmacology 235, 1093–1105 (2018). https://doi.org/10.1007/s00213-017-4827-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-017-4827-y