Declarative Memory

  • Wim J. RiedelEmail author
  • Arjan Blokland
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 228)


Declarative Memory consists of memory for events (episodic memory) and facts (semantic memory). Methods to test declarative memory are key in investigating effects of potential cognition-enhancing substances—medicinal drugs or nutrients. A number of cognitive performance tests assessing declarative episodic memory tapping verbal learning, logical memory, pattern recognition memory, and paired associates learning are described. These tests have been used as outcome variables in 34 studies in humans that have been described in the literature in the past 10 years. Also, the use of episodic tests in animal research is discussed also in relation to the drug effects in these tasks. The results show that nutritional supplementation of polyunsaturated fatty acids has been investigated most abundantly and, in a number of cases, but not all, show indications of positive effects on declarative memory, more so in elderly than in young subjects. Studies investigating effects of registered anti-Alzheimer drugs, cholinesterase inhibitors in mild cognitive impairment, show positive and negative effects on declarative memory. Studies mainly carried out in healthy volunteers investigating the effects of acute dopamine stimulation indicate enhanced memory consolidation as manifested specifically by better delayed recall, especially at time points long after learning and more so when drug is administered after learning and if word lists are longer. The animal studies reveal a different picture with respect to the effects of different drugs on memory performance. This suggests that at least for episodic memory tasks, the translational value is rather poor. For the human studies, detailed parameters of the compositions of word lists for declarative memory tests are discussed and it is concluded that tailored adaptations of tests to fit the hypothesis under study, rather than “off-the-shelf” use of existing tests, are recommended.


Declarative memory Episodic memory Cognition-enhancing drugs 


Declaration of Conflict of Interest

W. J. Riedel is part-time employed by Maastricht University and has in the past 12 months also carried out consultancy for Cambridge Cognition, Takeda, Lundbeck, and Keyview Labs.


  1. Allen TA, Fortin NJ (2013) The evolution of episodic memory. Proc Natl Acad Sci U S A 110(Suppl 2):10379–10386. doi: 10.1073/pnas.1301199110 CrossRefPubMedCentralPubMedGoogle Scholar
  2. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G et al (2007) Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 32(5):1011–1020. doi: 10.1038/sj.npp.1301227 CrossRefPubMedGoogle Scholar
  3. Balsters JH, O’Connell RG, Martin MP, Galli A, Cassidy SM, Kilcullen SM, Delmonte S et al (2011) Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers. PLoS One 6(9):e24126. doi: 10.1371/journal.pone.0024126 CrossRefPubMedCentralPubMedGoogle Scholar
  4. Benton D, Donohoe RT, Clayton DE, Long SJ (2013) Supplementation with DHA and the psychological functioning of young adults. Br J Nutr 109(1):155–161. doi: 10.1017/S0007114512000566 CrossRefPubMedGoogle Scholar
  5. Blokland A, van Goethem N, Heckman P, Schreiber R, Prickaerts J (2014) Translational issues with the development of cognition enhancing drugs. Front Neurol 5:190. doi: 10.3389/fneur.2014.00190 CrossRefPubMedCentralPubMedGoogle Scholar
  6. Brodziak A, Kolat E, Rozyk-Myrta A (2014) In search of memory tests equivalent for experiments on animals and humans. Med Sci Monit 20:2733–2739. doi: 10.12659/MSM.891056 CrossRefPubMedCentralPubMedGoogle Scholar
  7. Christmas D, Diaper A, Wilson S, Rich A, Phillips S, Udo de Haes J, Sjogren M, Nutt D (2014) A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers. Hum Psychopharmacol 29(2):163–171. doi: 10.1002/hup.2384 CrossRefPubMedGoogle Scholar
  8. Chuhan YS, Taukulis HK (2006) Impairment of single-trial memory formation by oral methylphenidate in the rat. Neurobiol Learn Mem 85(2):125–131. doi: 10.1016/j.nlm.2005.09.001 CrossRefPubMedGoogle Scholar
  9. Clayton NS, Bussey TJ, Dickinson A (2003) Can animals recall the past and plan for the future? Nat Rev Neurosci 4:685–691CrossRefPubMedGoogle Scholar
  10. Cole BJ, Jones GH, Turner JD (1994) 5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task. Psychopharmacology (Berl) 116:135–142CrossRefGoogle Scholar
  11. Crystal JD (2013) Remembering the past and planning for the future in rats. Behav Processes 93:39–49. doi: 10.1016/j.beproc.2012.11.014 CrossRefPubMedCentralPubMedGoogle Scholar
  12. Cutuli D, De Bartolo P, Caporali P, Laricchiuta D, Foti F, Ronci M, Rossi C et al (2014) n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice. Front Aging Neurosci 6:220. doi: 10.3389/fnagi.2014.00220 CrossRefPubMedCentralPubMedGoogle Scholar
  13. Dangour AD, Allen E, Elbourne D, Fasey N, Fletcher AE, Hardy P, Holder GE et al (2010) Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr 91(6):1725–1732. doi: 10.3945/ajcn.2009.29121 CrossRefPubMedGoogle Scholar
  14. de Bruin N, Pouzet B (2006) Beneficial effects of galantamine on performance in the object recognition task in Swiss mice: deficits induced by scopolamine and by prolonging the retention interval. Pharmacol Biochem Behav 85:253–260CrossRefPubMedGoogle Scholar
  15. de Lima MN, Presti-Torres J, Dornelles A, Scalco FS, Roesler R, Garcia VA, Schroder N (2011) Modulatory influence of dopamine receptors on consolidation of object recognition memory. Neurobiol Learn Mem 95(3):305–310. doi: 10.1016/j.nlm.2010.12.007 CrossRefPubMedGoogle Scholar
  16. de Rover M, Pironti VA, McCabe JA, Acosta-Cabronero J, Arana FS, Morein-Zamir S, Hodges JR et al (2011) Hippocampal dysfunction in patients with mild cognitive impairment: a functional neuroimaging study of a visuospatial paired associates learning task. Neuropsychologia 49(7):2060–2070. doi: 10.1016/j.neuropsychologia.2011.03.037 CrossRefPubMedGoogle Scholar
  17. Delis DC, Kramer JH, Kaplan E, Ober BA (1987) California verbal learning test manual. The Psychological Corporation, San Antonia, TXGoogle Scholar
  18. Dere E, Kart-Teke E, Huston JP, De Souza Silva MA (2006) The case for episodic memory in animals. Neurosci Biobehav Rev 30:1206–1224CrossRefPubMedGoogle Scholar
  19. Eichenbaum H, Fortin N, Sauvage M, Robitsek RJ, Farovik A (2010) An animal model of amnesia that uses Receiver Operating Characteristics (ROC) analysis to distinguish recollection from familiarity deficits in recognition memory. Neuropsychologia 48(8):2281–2289. doi: 10.1016/j.neuropsychologia.2009.09.015 CrossRefPubMedCentralPubMedGoogle Scholar
  20. Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res 31:47–59CrossRefPubMedGoogle Scholar
  21. Fouquet C, Tobin C, Rondi-Reig L (2010) A new approach for modeling episodic memory from rodents to humans: the temporal order memory. Behav Brain Res 215(2):172–179. doi: 10.1016/j.bbr.2010.05.054 CrossRefPubMedGoogle Scholar
  22. Gron G, Kirstein M, Thielscher A, Riepe MW, Spitzer M (2005) Cholinergic enhancement of episodic memory in healthy young adults. Psychopharmacology (Berl) 182(1):170–179. doi: 10.1007/s00213-005-0043-2 CrossRefGoogle Scholar
  23. Gron G, Brandenburg I, Wunderlich AP, Riepe MW (2006) Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. Neurobiol Aging 27(1):78–87. doi: 10.1016/j.neurobiolaging.2004.12.005 CrossRefPubMedGoogle Scholar
  24. Hermens DF, Cooper NJ, Clark CR, Debrota D, Clarke SD, Williams LM (2007) An integrative approach to determine the best behavioral and biological markers of methylphenidate. J Integr Neurosci 6(1):105–140CrossRefPubMedGoogle Scholar
  25. Izquierdo I, Bevilaqua LR, Rossato JI, Lima RH, Medina JH, Cammarota M (2008) Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration. Proc Natl Acad Sci U S A 105(49):19504–19507. doi: 10.1073/pnas.0810650105 CrossRefPubMedCentralPubMedGoogle Scholar
  26. Jackson PA, Deary ME, Reay JL, Scholey AB, Kennedy DO (2012) No effect of 12 weeks’ supplementation with 1 g DHA-rich or EPA-rich fish oil on cognitive function or mood in healthy young adults aged 18-35 years. Br J Nutr 107(8):1232–1243. doi: 10.1017/S000711451100403X CrossRefPubMedGoogle Scholar
  27. Karr JE, Grindstaff TR, Alexander JE (2012) Omega-3 polyunsaturated fatty acids and cognition in a college-aged population. Exp Clin Psychopharmacol 20(3):236–242. doi: 10.1037/a0026945 CrossRefPubMedGoogle Scholar
  28. Kesner RP, Hunsaker MR, Warthen MW (2008) The CA3 subregion of the hippocampus is critical for episodic memory processing by means of relational encoding in rats. Behav Neurosci 122(6):1217–1225. doi: 10.1037/a0013592 CrossRefPubMedGoogle Scholar
  29. King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (2004) 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation—an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47:195–204CrossRefPubMedGoogle Scholar
  30. Klaassen T, Riedel WJ, Deutz NEP, Van Praag HM (2002) Mood congruent memory bias induced by tryptophan depletion. Psychol Med 32(1):167–172CrossRefPubMedGoogle Scholar
  31. Kuypers KP, Ramaekers JG (2005) Transient memory impairment after acute dose of 75 mg 3.4-Methylene-dioxymethamphetamine. J Psychopharmacol 19(6):633–639CrossRefPubMedGoogle Scholar
  32. Lee LK, Shahar S, Chin AV, Yusoff NA (2013) Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology (Berl) 225(3):605–612. doi: 10.1007/s00213-012-2848-0 CrossRefGoogle Scholar
  33. Lezak MD (2004) Neuropsychological assessment, 3rd edn. Oxford University Press, New YorkGoogle Scholar
  34. Lieben CK, Blokland A, Sik A, Sung E, van Nieuwenhuizen P, Schreiber R (2005) The selective 5-HT(6) receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat. Neuropsychopharmacology 30:2169–2179CrossRefPubMedGoogle Scholar
  35. Liem-Moolenaar M, Zoethout RW, de Boer P, Schmidt M, de Kam ML, Cohen AF, Franson KL, van Gerven JM (2010) The effects of the glycine reuptake inhibitor R213129 on the central nervous system and on scopolamine-induced impairments in psychomotor and cognitive function in healthy subjects. J Psychopharmacol 24(11):1671–1679. doi: 10.1177/0269881109106942 CrossRefPubMedGoogle Scholar
  36. Linssen AM, Vuurman EF, Sambeth A, Riedel WJ (2012) Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers. Psychopharmacology (Berl) 221(4):611–619. doi: 10.1007/s00213-011-2605-9 CrossRefGoogle Scholar
  37. Linssen AM, Sambeth A, Vuurman EF, Riedel WJ (2014) Cognitive effects of methylphenidate and levodopa in healthy volunteers. Eur Neuropsychopharmacol 24(2):200–206. doi: 10.1016/j.euroneuro.2013.09.009 CrossRefPubMedGoogle Scholar
  38. Mehta MA, Riedel WJ (2006) Dopaminergic enhancement of cognitive function. Curr Pharm Des 12(20):2487–2500CrossRefPubMedGoogle Scholar
  39. Morris RG (2001) Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease. Philos Trans R Soc Lond B Biol Sci 356(1413):1453–1465. doi: 10.1098/rstb.2001.0945 CrossRefPubMedCentralPubMedGoogle Scholar
  40. Muller U, Rowe JB, Rittman T, Lewis C, Robbins TW, Sahakian BJ (2013) Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. Neuropharmacology 64:490–495. doi: 10.1016/j.neuropharm.2012.07.009 CrossRefPubMedCentralPubMedGoogle Scholar
  41. Naudon L, Hotte M, Jay TM (2007) Effects of acute and chronic antidepressant treatments on memory performance: a comparison between paroxetine and imipramine. Psychopharmacology (Berl) 191(2):353–364. doi: 10.1007/s00213-006-0660-4 CrossRefGoogle Scholar
  42. Pitsikas N, Rigamonti AE, Cella SG, Muller EE (2003) The 5-HT 1A receptor antagonist WAY 100635 improves rats performance in different models of amnesia evaluated by the object recognition task. Brain Res 983(1–2):215–222CrossRefPubMedGoogle Scholar
  43. Prickaerts J, Sik A, Van Der Staay FJ, De Vente J, Blokland A (2005) Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation. Psychopharmacology (Berl) 177:381–390CrossRefGoogle Scholar
  44. Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, File SE (2005) Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived? J Clin Psychopharmacol 25(2):175–179CrossRefPubMedGoogle Scholar
  45. Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J (2009) Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology (Berl) 202(1–3):419–443. doi: 10.1007/s00213-008-1273-x CrossRefGoogle Scholar
  46. Reneerkens OA, Sambeth A, Ramaekers JG, Steinbusch HW, Blokland A, Prickaerts J (2013) The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral-electroencephalography study. J Psychopharmacol 27(7):600–608. doi: 10.1177/0269881113477747 CrossRefPubMedGoogle Scholar
  47. Rey A (1958) L’examen psychologique dans les cas d’encéphalopathie traumatique. Presses Universitaires de France, ParisGoogle Scholar
  48. Riby LM, McMurtrie H, Smallwood J, Ballantyne C, Meikle A, Smith E (2006) The facilitative effects of glucose ingestion on memory retrieval in younger and older adults: is task difficulty or task domain critical? Br J Nutr 95(2):414–420CrossRefPubMedGoogle Scholar
  49. Riedel WJ (2014) Preventing cognitive decline in preclinical Alzheimer’s disease. Curr Opin Pharmacol 14:18–22. doi: 10.1016/j.coph.2013.10.002 CrossRefPubMedGoogle Scholar
  50. Riedel WJ, Klaassen T, Deutz NEP, Van Someren A, Van Praag HM (1999) Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl) 141(4):362–369CrossRefGoogle Scholar
  51. Rock PL, Roiser JP, Riedel WJ, Blackwell AD (2014) Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med 44(10):2029–2040. doi: 10.1017/S0033291713002535 CrossRefGoogle Scholar
  52. Sahakian BJ, Morris RG, Evenden JL, Heald A, Levy R, Philpot M, Robbins TW (1988) A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson’s disease. Brain 111(Pt 3):695–718CrossRefPubMedGoogle Scholar
  53. Sambeth A, Riedel W, Smits L, Blokland A (2007) Cholinergic drugs affect novel object recognition in rats: relation with hippocampal EEG? Eur J Pharmacol 572:151–159CrossRefPubMedGoogle Scholar
  54. Sambeth A, Riedel WJ, Klinkenberg I, Kahkonen S, Blokland A (2014) Biperiden selectively induces memory impairment in healthy volunteers: no interaction with citalopram. Psychopharmacology (Berl). doi: 10.1007/s00213-014-3822-9 Google Scholar
  55. Schmitt JAJ, Jorissen BL, Dye L, Markus CR, Deutz NEP, Riedel WJ (2005) Memory function in women with premenstrual complaints and the effect of serotonergic stimulation by acute administration of an alpha-lactalbumin protein. J Psychopharmacol 19(4):375–384CrossRefPubMedGoogle Scholar
  56. Squire LR (1987) Memory and brain. Oxford University Press, New YorkGoogle Scholar
  57. Squire LR (2004) Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem 82(3):171–177CrossRefPubMedGoogle Scholar
  58. Stonehouse W, Conlon CA, Podd J, Hill SR, Minihane AM, Haskell C, Kennedy D (2013) DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial. Am J Clin Nutr 97(5):1134–1143. doi: 10.3945/ajcn.112.053371 CrossRefPubMedGoogle Scholar
  59. Stough C, Kure C, Tarasuik J, Lloyd J, Downey LA, Scholey A, Wesnes KA (2009) A randomized, double-blind, placebo controlled study examining the effects of a combination nutraceutical formula on cognitive functioning and mood. JANA 12(1):12–19Google Scholar
  60. Stough C, Downey L, Silber B, Lloyd J, Kure C, Wesnes K, Camfield D (2012) The effects of 90-day supplementation with the omega-3 essential fatty acid docosahexaenoic acid (DHA) on cognitive function and visual acuity in a healthy aging population. Neurobiol Aging 33(4):824.e821–e823. doi: 10.1016/j.neurobiolaging.2011.03.019 CrossRefGoogle Scholar
  61. Talpos JC, Winters BD, Dias R, Saksida LM, Bussey TJ (2009) A novel touchscreen-automated paired-associate learning (PAL) task sensitive to pharmacological manipulation of the hippocampus: a translational rodent model of cognitive impairments in neurodegenerative disease. Psychopharmacology (Berl) 205(1):157–168. doi: 10.1007/s00213-009-1526-3 CrossRefGoogle Scholar
  62. Templer VL, Hampton RR (2013) Episodic memory in nonhuman animals. Curr Biol 23(17):R801–R806. doi: 10.1016/j.cub.2013.07.016 CrossRefPubMedCentralPubMedGoogle Scholar
  63. Theunissen EL, Street D, Hojer AM, Vermeeren A, van Oers A, Ramaekers JG (2013) A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition. Clin Pharmacol Ther 93(6):493–501. doi: 10.1038/clpt.2013.39 CrossRefPubMedGoogle Scholar
  64. Theunissen EL, Heckman P, de Sousa Fernandes Perna EB, Kuypers KP, Sambeth A, Blokland A, Prickaerts J, Toennes SW, Ramaekers JG (2014) Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans. Psychopharmacology (Berl). doi: 10.1007/s00213-014-3667-2 Google Scholar
  65. Tulving E (1972) Episodic and semantic memory. In: Tulving E, Donaldson W (eds) Organization of memory. Academic, New YorkGoogle Scholar
  66. Tulving E (2002) Episodic memory: from mind to brain. Annu Rev Psychol 53:1–25. doi: 10.1146/annurev.psych.53.100901.135114 CrossRefPubMedGoogle Scholar
  67. Vakhapova V, Cohen T, Richter Y, Herzog Y, Korczyn AD (2010) Phosphatidylserine containing omega-3 fatty acids may improve memory abilities in non-demented elderly with memory complaints: a double-blind placebo-controlled trial. Dement Geriatr Cogn Disord 29(5):467–474. doi: 10.1159/000310330 CrossRefPubMedGoogle Scholar
  68. Valluzzi JA, Chan K (2007) Effects of fluoxetine on hippocampal-dependent and hippocampal-independent learning tasks. Behav Pharmacol 18(5–6):507–513. doi: 10.1097/FBP.0b013e3282ee2a91 CrossRefPubMedGoogle Scholar
  69. van Ruitenbeek P, Mehta MA (2013) Potential enhancing effects of histamine H(1) agonism/H(3) antagonism on working memory assessed by performance and bold response in healthy volunteers. Br J Pharmacol 170(1):144–155. doi: 10.1111/bph.12184 CrossRefPubMedCentralPubMedGoogle Scholar
  70. Wechsler D (1997) Wechsler memory scale, 3rd edn. Psychological Corporation, San Antonio, TXGoogle Scholar
  71. Wingen M, Langer S, Ramaekers JG (2006) Verbal memory performance during subchronic challenge with a selective serotonergic and a mixed action antidepressant. Hum Psychopharmacol 21(7):473–479CrossRefPubMedGoogle Scholar
  72. Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M, Investigators M (2010) Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement 6(6):456–464. doi: 10.1016/j.jalz.2010.01.013 CrossRefPubMedGoogle Scholar
  73. Zeeuws I, Soetens E (2007) Verbal memory performance improved via an acute administration of D-amphetamine. Hum Psychopharmacol 22(5):279–287. doi: 10.1002/hup.848 CrossRefPubMedGoogle Scholar
  74. Zeeuws I, Deroost N, Soetens E (2010a) Effect of an acute d-amphetamine administration on context information memory in healthy volunteers: evidence from a source memory task. Hum Psychopharmacol 25(4):326–334. doi: 10.1002/hup.1120 CrossRefPubMedGoogle Scholar
  75. Zeeuws I, Deroost N, Soetens E (2010b) Verbal memory improved by D-amphetamine: influence of the testing effect. Hum Psychopharmacol 25(5):377–387. doi: 10.1002/hup.1128 CrossRefPubMedGoogle Scholar
  76. Zhang M, Moon C, Chan GC, Yang L, Zheng F, Conti AC, Muglia L, Muglia LJ, Storm DR, Wang H (2008) Ca-stimulated type 8 adenylyl cyclase is required for rapid acquisition of novel spatial information and for working/episodic-like memory. J Neurosci 28(18):4736–4744. doi: 10.1523/JNEUROSCI.1177-08.2008 CrossRefPubMedCentralPubMedGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Neuropsychology & Psychopharmacology, Faculty of Psychology & NeuroscienceMaastricht UniversityMaastrichtThe Netherlands

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