Increasing Dopamine and Acetylcholine Levels during Encoding Does Not Modulate Remember or Know Responses during Memory Retrieval in Healthy Aging—a Randomized Controlled Feasibility Study

Abstract

The retrieval of information from long-term memory can be associated with information regarding sources or context (recollection) or without further context (familiarity). The retrieval type depends on how information has been encoded previously, and this encoding process is supposed to be modulated by the neurotransmitters dopamine and acetylcholine. For example, acetylcholine levels in the hippocampus increase when one is confronted with novel information allowing for better encoding and, presumably, for retrieval of more detailed memories (recollection). On the other hand, a dopaminergic deficit such as in Parkinson’s disease has been shown to induce deficits in familiarity rather than in recollection-based retrieval. It is, however, unclear whether this finding arises from alterations in encoding, retrieval, or both. Moreover, other research has challenged this clear-cut dichotomy and linked dopamine to both familiarity and recollection, and acetylcholine to unspecific enhancement of memory for novel information. Thirty-nine healthy seniors (age range 62–77) participated in a remember/know task in which scenes that were presented with different repetition rates had to be encoded and retrieved on the following day. Neurotransmitter levels were modulated during encoding by administrating either levodopa (100 mg, N = 13) or galantamine (8 mg, N = 13) to one of two experimental groups. A third group received a placebo (N = 13). Across all groups, recognition memory increased as a function of stimulus repetition, and this effect was specifically pronounced for remember relative to know answers. Importantly, the drugs had no effect on recollection, familiarity, or overall recognition memory. The findings argue against a simple dichotomy of dopaminergic and cholinergic contributions to either recollection- or familiarity-based memory retrieval.

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References

  1. Bäckman, L., Nyberg, L., Lindenberger, U., Li, S.-C., & Farde, L. (2006). The correlative triad among aging, dopamine, and cognition: Current status and future prospects. Neuroscience & Biobehavioral Reviews, 30(6), 791–807.

    Article  Google Scholar 

  2. Barnes, L., Boubert, L., Harris, J., Lee, A., & David, A. S. (2003). Reality monitoring and visual hallucinations in Parkinson’s disease. Neuropsychologia, 41(5), 565–574.

    PubMed  Article  Google Scholar 

  3. Blatt, J., Vellage, A.-K., Baier, B., & Müller, N. (2014). The contribution of acetylcholine and dopamine to subprocesses of visual working memory—what patients with amnestic mild cognitive impairment and Parkinson’s disease can tell us. Neuropsychologia, 61, 89–95.

    PubMed  Article  Google Scholar 

  4. Bloemendaal, M., Froböse, M. I., Wegman, J., Zandbelt, B., van de Rest, O., Cools, R., & Aarts, E. (2018). Neuro-cognitve effects of tyrosine administration on reactive and proactive response inhibition in healthy older adults. eNeuro., 5(2), ENEURO.0035-17.2018. https://doi.org/10.1523/ENEURO.0035-17.2018.

    PubMed  PubMed Central  Article  Google Scholar 

  5. Bunzeck, N., Guitart-Masip, M., Dolan, R. J., & Duzel, E. (2014). Pharmacological dissociation of novelty responses in the human brain. Cerebral Cortex, 24(5), 1351–1360 Bhs420.

    PubMed  Article  Google Scholar 

  6. Chowdhury, R., Guitart-Masip, M., Bunzeck, N., Dolan, R. J., & Düzel, E. (2012). Dopamine modulates episodic memory persistence in old age. Journal of Neuroscience, 32(41), 14193–14204.

    PubMed  Article  Google Scholar 

  7. Cools, R., & D'Esposito, M. (2011). Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biological Psychiatry, 69(12), 113–125.

    Article  Google Scholar 

  8. Davidson, P. S. R., Anaki, D., Saint-Cyr, J. A., Chow, T. W., & Moscovitch, M. (2006). Exploring the recognition memory deficit in Parkinson’s disease: Estimates of recollection versus familiarity. Brain, 129, 1786–1779.

    Article  Google Scholar 

  9. Dewhurst, S. A., & Anderson, S. J. (1999). Effects of exact and category repetition in true and false recognition memory. Memory and Cognition, 27(4), 664–673.

    Article  Google Scholar 

  10. DGN. (2016). S3-Leitlinie Idiopathisches Parkinson-Syndrom: Springer. Heidelberg: Berlin.

    Google Scholar 

  11. DGPPN & DGN. (2017). S3-Leitlinie Demenzen. Berlin, Heidelberg: Springer Berlin Heidelberg.

    Google Scholar 

  12. Dumas, J. A., & Newhouse, P. A. (2011). The cholinergic hypothesis of cognitive aging revisited again: Cholinergic functional compensation. Pharmacology Biochemistry and Behavior, 99(2), 254–261.

    Article  Google Scholar 

  13. Dunn, J. C. (1996). Remember-know: A matter of confidence. Psychological Review, 111(2), 524.

    Article  Google Scholar 

  14. Eckart, C., Woźniak-Kwaśniewska, A., Herweg, N. A., Fuentenmilla, L., & Bunzeck, N. (2016). Acetylcholine modulates human working memory and subsequent familiarity based recognition via alpha oscillations. Neuroimage, 137, 61–69.

    PubMed  Article  Google Scholar 

  15. Edelstyn, N. M., Mayes, A. E., Condon, L., Tunnicliffe, M., & Ellis, S. J. (2007). Recognition, recollection, familiarity and executive function in medicated patients with moderate Parkinson’s disease. Journal of Neuropsychology, 1(2), 131–147.

    PubMed  Article  Google Scholar 

  16. Edelstyn, N. M., Shepherd, T. A., Mayes, A. R., Sherman, S. M., & Ellis, S. J. (2010). Effect of disease severity and dopaminergic medication on recollection and familiarity in patients with idiopathic nondementing Parkinson’s. Neuropsychologia, 48(5), 1367–1375.

    PubMed  Article  Google Scholar 

  17. Edelstyn, N. M., John, C. M., Shepherd, T. A., Drakeford, J. L., Clark-Carter, D., Ellis, S. M., & Mayes, A. R. (2015). Evidence of an amnesia-like cued-recall memory impairment in nondementing idiopathic Parkinson’s disease. Cortex, 71, 85–101.

    PubMed  Article  Google Scholar 

  18. Eichenbaum, H. E., & Cohen, N. J. (2001). From Conditioning to Conscious Recollection: Memory Systems of the Brain (Colume 35). Oxford: University Press.

    Google Scholar 

  19. Eichenbaum, H. E., Yonelinas, A. R., & Ranganath, C. (2007). The medial temporal loba and recognition memory. Annual Review of Neuroscience, 30, 123–152.

    PubMed  PubMed Central  Article  Google Scholar 

  20. Froeliger, B., Gilbert, D. G., & McClernon, F. J. (2009). Effects of nicotine on novelty detection and memory recognition performance: Double-blind, placebo-controlled studies of smokers and non-smokers. Psychopharmacology, 205(4), 625–633.

    PubMed  Article  Google Scholar 

  21. Gasbarri, A., Packard, M. G., Campana, E., & Pacitti, C. (1994). Anterograde and retrograde tracing of projections from the ventral tegmental area to the hippocampal formation in the rat. Brain Research Bulletin, 33(4), 445–452.

    PubMed  Article  Google Scholar 

  22. Hasselmo, M. E. (2006). The role of acetylcholine in learning and memory. Current Opinion in Neurobiology, 16(6), 710–715.

    PubMed  PubMed Central  Article  Google Scholar 

  23. Heathcote, A., Frances, R., & Dunn, J. (2006). Recollection and familiarity in recognition memory: Evidence from ROC curves. Journal of Memory and Language, 55(4), 495–514.

    Article  Google Scholar 

  24. Karrer, T. M., Josef, A. K., Mata, R., Morris, E. D., & Samanez-Larkin, G. R. (2017). Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: A meta-analysis. Neurobiology of Aging, 57, 36–46.

    PubMed  PubMed Central  Article  Google Scholar 

  25. Knecht, S., Breitenstein, C., Bushuven, S., Wailke, S., Kamping, S., Flöel, A., Zwitserlood, P., & Ringelstein, E. B. (2004). Levodopa: Faster and better word learning in normal humans. Annals of Neurology, 56(1), 20–26.

    PubMed  Article  Google Scholar 

  26. Koen, J. D., & Yonelinas, A. P. (2014). The effects of healthy aging, amnestic mild cognitive impairment, and Alzheimer’s disease on recollection and familiarity: A meta-analytic review. Neuropsychology Review, 24(3), 332–354.

    PubMed  PubMed Central  Article  Google Scholar 

  27. Li, S.-C., Lindenberger, U., & Bäckman, L. (2010). Dopaminergic modulation of cognition across the life span. Neuroscience & Biobehavioral Reviews, 34(5), 625–630.

    Article  Google Scholar 

  28. Libby, L. A., Yonelinas, A. P., Ranganath, C., & Ragland, J. D. (2013). Recollection and familiarity in schizophrenia: A quantitative review. Biological Psychiatry, 73(10), 944–950.

    PubMed  Article  Google Scholar 

  29. Mäntylä, T. (1993). Knowing but not remembering: Adult age differences in recollective experience. Memory & Cognition, 21(3), 379–388.

    Article  Google Scholar 

  30. Mesulam, M.-M. (2004). The cholinergic innervation of the human cerebral cortex. Progress in Brain Research, 145, 67–78.

    PubMed  Article  Google Scholar 

  31. Monte-Silva, K., Kuo, M.-F., Thirugnanasambandam, N., Liebetanz, D., Paulus, W., & Mitsche, M. A. (2009). Dose-dependent inverted U-shaped effects of dopamine (D2-like) receptor activation on focal and nonfocal plasticity in humans. The Journal of Neuroscience, 29(19), 6124–6131.

    PubMed  PubMed Central  Article  Google Scholar 

  32. Morcom, A. M., Bullmore, E. T., Huppert, F. A., Lennox, B., Praseedom, A., Linnington, H., & Fletcher, P. C. (2010). Memory encoding and dopamine in the aging brain: A psychopharmacological neuroimaging study. Cerebral Cortex, 20(3), 743–757.

    PubMed  Article  Google Scholar 

  33. Naveh-Benjamin, M. (2000). Adult age differences in memory performance: Tests of an associative deficit hypothesis. Journal of Experimental Psychology: Learning, Memory, and Cognition, 26(5), 1170–1187.

    PubMed  Google Scholar 

  34. Paller, K. A., & Wagner, A. D. (2002). Observing the transformation of experience into memory. Trends in Cognitive Science, 6(2), 93–102.

    Article  Google Scholar 

  35. Parkin, A. J., Gardiner, J. M., & Rosser, R. (1995). Functional aspects of recollective experience in face recognition. Consciousness and Cognition, 4(4), 387–398.

    PubMed  Article  Google Scholar 

  36. Perfect, T., & Dasgupta, Z. R. R. (1997). What underlies the deficit in reported recollective experience in old age? Memory & Cognition, 25(6), 849–858.

    Article  Google Scholar 

  37. Pitarque, A., Sales, A., Meléndez, J. C., & Algarabel, S. (2015). Repetition increases false recollection in older people. Scandinavian Journal of Psychology, 56(1), 28–44.

    Article  Google Scholar 

  38. Samson, Y., Wu, J. J., Friedmann, A. H., & Davis, J. N. (1990). Catecholaminergic innervation of the hippocampus in the cynomolgus monkey. Journal of Comparative Neurology, 298(2), 250–263.

    PubMed  Article  Google Scholar 

  39. Shepherd, T. A., Edelstyn, N. M., Mayes, A. R., & Ellis, S. J. (2013). Second-generation dopamine agonists and recollection impairments in Parkinson’s disease. Journal of Neuropsychology, 7(2), 284–305.

    PubMed  Article  Google Scholar 

  40. Störmer, V. S., Passow, S., Biesenack, J., & Li, S.-C. (2012). Dopaminergic and cholinergic modulations of visual-spatial attention and working memory: Insights from molecular genetic research and implications for adult cognitive development. Developmental Psychology, 48(3), 875–889.

    PubMed  Article  Google Scholar 

  41. Tulving, E., & Markowitsch, H. J. (1998). Episodic and declarative memory: Role of the hippocampus. Hippocampus, 8(3), 198–204.

    PubMed  Article  Google Scholar 

  42. Tulving, E., & Thomson, D. M. (1973). Encoding specifity and retrieval processes in episodic memory. Psychological Review, 80(5), 352–373.

    Article  Google Scholar 

  43. Welsh, K. A., Butters, N., Mohs, R. C., et al. (1994). The consortium to establish a registry for Alzheimer’s disease (CERAD). Part V. a normative study of the neuropsychological battery. Neurology, 44(4), 609–614.

    PubMed  Article  Google Scholar 

  44. Wixted, J. T., & Mickes, L. (2010). A continuous dual-process model of remember/know judgments. Psychological Review, 117(4), 1025–1054.

    PubMed  Article  Google Scholar 

  45. Yesavage, J. A., Brink, T. L., Rose, T. L., Lum, O., Huang, V., Adey, M., & Leirer, O. (1983). Development and validation of a geriatric depression screening scale: A preliminary report. Journal of Psychiatric Research, 17(1), 37–49.

    Article  Google Scholar 

  46. Yonelinas, A. P. (2002). The nature of recollection and familiarity: A review of 30 years of research. Journal of Memory and Language, 46(3), 441–517.

    Article  Google Scholar 

  47. Yonelinas, A. P., & Jacoby, L. L. (2012). The process-dissociation approach two decades later: Convergence, boundary conditions, and new directions. Memory and Cognition, 40(5), 663–680.

    PubMed  Article  Google Scholar 

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Acknowledgements

This work was supported by the DFG (Deutsche Forschungsgesellschaft) grant Mu1364/4-1 and Mu1364/4-2 to Prof. Dr. Müller. We thank Freya-Sophie Lenz for helping with the assessment of data.

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Vellage, A.K., Müller, P., Graf, A. et al. Increasing Dopamine and Acetylcholine Levels during Encoding Does Not Modulate Remember or Know Responses during Memory Retrieval in Healthy Aging—a Randomized Controlled Feasibility Study. J Cogn Enhanc 3, 328–337 (2019). https://doi.org/10.1007/s41465-019-00122-x

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Keywords

  • Recognition memory
  • Dopamine
  • Acetylcholine
  • Aging
  • Retrieval