Psychopharmacology

, Volume 188, Issue 4, pp 462–471

Midazolam does not inhibit association formation, just its storage and strengthening

  • Lynne M. Reder
  • Iain Proctor
  • John R. Anderson
  • Ferenc Gyulai
  • Joseph J. Quinlan
  • Joyce M. Oates
Original Investigation

Abstract

Rationale

Although there have been many studies examining the effects of benzodiazepines on memory performance, their effects on working memory are equivocal and little is known about whether they affect the efficacy of practice of already learned material.

Objectives

The objectives in two experiments were to examine (a) whether midazolam impairs performance on a working memory task designed to minimize mnemonic strategies such as rehearsal or chunking of information to be recalled and (b) the effect of midazolam on repeated practice of paired associates that were learned before drug administration.

Materials and methods

Both experiments involved subcutaneous administration of 0.03 mg of saline or midazolam per kilogram of bodyweight in within-subject, placebo-controlled designs, involving 23 subjects in (a) and 31 in (b).

Results

The drug had no effect on the ability to recall the digits in serial order even though the encoding task prevented the digits from being rehearsed or maintained in an articulatory buffer. Paired associates that were learned before the injection showed a benefit of subsequent practice under saline but not under midazolam.

Conclusions

The results suggest that (a) midazolam does not affect the formation of new associations in short-term memory provided that the presentation rate is not too fast to form these associations when sedated, despite the evidence that the drug blocks long-term memory (LTM) retention of associations; and (b) the potential for over-learning with practice of learned associations in LTM is adversely affected by midazolam such that repeated exposures do not strengthen new learning.

Keywords

Benzodiazepine Working memory Memory Binding Paired associate learning Practice MODS task Midazolam Over-learning Digit span 

References

  1. Anderson JR, Reder LM, Lebiere C (1996) Working memory: activation limitations on retrieval. Cogn Psychol 30:221–256CrossRefPubMedGoogle Scholar
  2. Bacon E, Danion JM, Kauffmann-Muller F, Schelstraete MA, Bruant A, Sellal F, Grande D (1998) Confidence level and feeling of knowing for episodic and semantic memory: an investigation of lorazepam effects on metamemory. Psychopharmacology 138:318–325PubMedCrossRefGoogle Scholar
  3. Baddeley AD (1986) Working memory. Oxford University Press, Oxford, EnglandGoogle Scholar
  4. Barrett LF, Tugade MM, Engle RW (2004) Individual differences in working memory capacity and dual-process theories of the mind. Psychol Bull 130(4):553–573PubMedCrossRefGoogle Scholar
  5. Blin O, Simon N, Jouve E, Habib M, Gayraud D, Durand A et al (2001) Pharmacokinetic and pharmacodynamic analysis of sedative and amnesic effects of lorazepam in healthy volunteers. Clin Neuropharmacol 24(2):71–81PubMedCrossRefGoogle Scholar
  6. Blumenfeld RS, Ranganath C (2006) Dorsolateral prefrontal cortex promotes long term memory formation through its role in working memory organization. J Neurosci 26(3):916–925PubMedCrossRefGoogle Scholar
  7. Buffett-Jerrott SE, Stewart SH, Finley GA, Loughlan HL (2003) Effects of benzodiazepines on explicit memory in a paediatric surgery setting. Psychopharmacology 168:377–386PubMedCrossRefGoogle Scholar
  8. Caplan D, Rochon E, Waters GS (1992) Articulatory and phonological determinants of word length effects in span tasks. Q J Exp Psychol 45(2):177–192Google Scholar
  9. Cohen JD, O’Reilly RC (1996) A preliminary theory of the interactions between prefrontal cortex and hippocampus that contribute to planning and prospective memory. In: Brandimonte M, Einstein GO, McDaniel MA (eds) Prospective memory: theory and applications. Erlbaum, Mahwah, NJ, pp 267–295Google Scholar
  10. Cohen JD, Braver TS, O’Reilly RC (1996) A computational approach to pre-frontal cortex, cognitive control, and schizophrenia: recent developments and current challenges. Philos Trans R Soc Lond B Biol Sci 351:1515–1527PubMedGoogle Scholar
  11. Conway AR, Engle RW (1996) Individual differences in working memory capacity: more evidence for a general capacity theory. Memory 4(6):577–590PubMedGoogle Scholar
  12. Curran HV, Birch B (1991) Differentiating the sedative, psychomotor and amnesic effects of benzodiazepines: a study with midazolam and the benzodiazepine antagonist, flumazenil. Psychopharmacology 103(4):519–523PubMedCrossRefGoogle Scholar
  13. Daily LZ, Lovett MC, Reder LM (2001) Modeling individual differences in working memory performance: a source activation account. Cogn Sci 25:315–353CrossRefPubMedGoogle Scholar
  14. Daneman M, Carpenter P (1980) Individual differences in working memory and reading. J Verbal Learn Verbal Behav 19:450–466CrossRefGoogle Scholar
  15. Davachi L, Wagner AD (2002) Hippocampal contributions to episodic encoding: insights from relational and item-based learning. J Neurophysiol 88:982–990PubMedGoogle Scholar
  16. Davachi L, Mitchell JP, Wagner AD (2003) Multiple routes to memory: distinct medial temporal lobe processes build item and source memories. Proc Natl Acad Sci USA 100:2157–2162PubMedCrossRefGoogle Scholar
  17. D’Esposito M, Detre JA, Alsop DC, Shin RK, Atlas S, Grossman M (1995) The neural basis of the central executive system of working memory. Nature 378:279–281PubMedCrossRefGoogle Scholar
  18. Diana RA, Reder LM (in press) The low frequency encoding disadvantage: word frequency affects processing demands. J Exp Psychol Learn Mem CognGoogle Scholar
  19. Ebbinghaus H (1913) Memory: a contribution to experimental psychology. Teachers College, Columbia University, New York (reprinted Thoemmes, Bristol, 1999)Google Scholar
  20. Eichenbaum H, Cohen NJ (2001) From conditioning to conscious recollection: memory systems of the brain. Oxford University Press, New YorkGoogle Scholar
  21. Fisher J, Hirshman E, Henthorn T, Arndt J, Passannante A (2006) Midazolam amnesia and short-term/working memory processes. Conscious Cogn 15(1):54–63PubMedCrossRefGoogle Scholar
  22. Fleishaker JC, Garzone PD, Chambers JH, Sirocco K, Weingartner H (1995) Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects. Psychopharmacology 120:169–176PubMedCrossRefGoogle Scholar
  23. Gabrieli JDE, Keane MM, Zarella MM, Poldrack RA (1997) Preservation of implicit memory for new associations in global amnesia. Psychol Sci 8(4):326–329CrossRefGoogle Scholar
  24. Ghoneim MM (2004a) Drugs and human memory (part 1): clinical, theoretical, and methodologic issues. Anesthesiology 100(4):987–1002PubMedCrossRefGoogle Scholar
  25. Ghoneim MM (2004b) Drugs and human memory (part 2): Clinical, theoretical, and methodologic issues. Anesthesiology 100(5):1277–1297PubMedCrossRefGoogle Scholar
  26. Ghoneim MM, Mewaldt SP (1975) Effects of diazepam and scopolamine on storage, retrieval and organizational processes in memory. Psychopharmacologia 44(3):257–262PubMedCrossRefGoogle Scholar
  27. Ghoneim MM, Mewaldt SP (1990) Benzodiazepines and human memory: a review. Anesthesiology 72(5):926–938PubMedCrossRefGoogle Scholar
  28. Goshen-Gottstein Y, Moscovitch M, Melo B (2000) Intact implicit memory for newly formed verbal associations in amnesic patients following single study trials. Neuropsychology 14(4):570–578PubMedCrossRefGoogle Scholar
  29. Hennessy MJ, Kirkby KC, Montgomery IM (1991) Comparison of the amnesic effects of midazolam and diazepam. Psychopharmacology 103(4):545–550PubMedCrossRefGoogle Scholar
  30. Hinrichs JV, Mewaldt SP, Ghoneim MM, Berie JL (1982) Diazepam and learning: assessment of acquisition deficits. Pharmacol Biochem Behav 17(1):165–170PubMedCrossRefGoogle Scholar
  31. Hirshman E, Passannante A, Henzler A (1999) The effect of midazolam on implicit memory tests. Brain Cogn 41:351–364PubMedCrossRefGoogle Scholar
  32. Hirshman E, Passannante A, Arndt J (2001) Midazolam amnesia and conceptual processing in implicit memory. J Exp Psychol Gen 130(3):453–465PubMedCrossRefGoogle Scholar
  33. Hirshman E, Fisher J, Henthorn T, Arndt J, Passannante A (2002) Midazolam amnesia and the dual-process models of the word-frequency mirror effect. J Mem Lang 47:499–516CrossRefGoogle Scholar
  34. Hunt RR, Einstein GO (1981) Relational and item-specific information in memory. J Verbal Learn Verbal Behav 20:497–514CrossRefGoogle Scholar
  35. Kirkby KC, Montgomery IM, Badcock R, Daniels BA (1995) A comparison of age-related deficits in memory and frontal lobe function following oral lorazepam administration. J Psychopharmacol 9(4):319–325Google Scholar
  36. Knopman D (1991) Unaware learning versus preserved learning in pharmacologic amnesia: similarities and differences. J Exper Psychol Learn Mem Cogn 17(5):1017–1029CrossRefGoogle Scholar
  37. Loke WH, Hinrichs JV, Ghoneim MM (1985) Caffeine and diazepam: separate and combined effects on mood, memory, and psychomotor performance. Psychopharmacology 87:344–350PubMedCrossRefGoogle Scholar
  38. Lovett MC, Reder LM, Lebiere C (1997) Modeling individual differences in a digit working memory task. Proceedings of the Nineteenth Annual Cognitive Science Conference. Mahwah, NJ: Erlbaum, 460–465Google Scholar
  39. Lovett MC, Reder LM, Lebiere C (1999) Modeling working memory in a unified architecture: an ACT-R perspective. In: Miyake A, Shah P (eds) Models of working memory. Cambridge University Press, pp 135–182Google Scholar
  40. Lovett MC, Daily LZ, Reder LM (2000) A source activation theory of working memory: cross-task prediction of performance in ACT-R. Journal of Cognitive Systems Research 1:99–118CrossRefGoogle Scholar
  41. Mallick JL, Kirby KC, Martin F, Philip M, Hennessy MJ (1993) A comparison of the amnesic effects of lorazepam in alcoholics and nonalcoholics. Psychopharmacology 110(1–2):181–186PubMedCrossRefGoogle Scholar
  42. McClelland JL, McNaughton BL, O’Reilly RC (1995) Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev 102:419–457PubMedCrossRefGoogle Scholar
  43. Miller EK, Freedman DJ, Wallis JD (2003) The prefrontal cortex: categories, concepts and cognition. In: Parker A, Derrington A, Blamore C (eds) The physiology of cognitive processes. Oxford University Press, New York, NY, pp 252–273Google Scholar
  44. Milner B (2005) The medial temporal-lobe amnesic syndrome. Psychiatr Clin North Am 28(3):599–611PubMedCrossRefGoogle Scholar
  45. Mintzer MZ (2003) Triazolam-induced amnesia and the word-frequency effect in recognition memory: support for a dual process account. J Mem Lang 48:596–602CrossRefGoogle Scholar
  46. Mintzer MZ, Griffiths RR (2003a) Lorazepam and scopolamine: a single-dose comparison of effects on human memory and attentional processes. Exp Clin Psychopharmacol 11(1):56–72PubMedGoogle Scholar
  47. Mintzer MZ, Griffiths RR (2003b) Triazolam–amphetamine interaction: dissociation of effects on memory versus arousal. J Psychopharmacol 17(1):17–29PubMedCrossRefGoogle Scholar
  48. Mintzer MZ, Griffiths RR, Contoreggi C, Kimes AS, London ED, Ernst M (2001) Effects of triazolam on brain activity during episodic memory encoding: a PET study. Neuropsychopharmacology 25(5):744–756PubMedCrossRefGoogle Scholar
  49. Nissley HM, Schmitter-Edgecombe M (2002) Perceptually based implicit learning in severe closed-head injury patients. Neuropsychology 16(1):111–122PubMedCrossRefGoogle Scholar
  50. Oberauer K, Lange E, Engle RW (2004) Working memory capacity and resistance to interference. J Mem Lang 51(1):80–96CrossRefGoogle Scholar
  51. Park H, Quinlan JJ, Thornton ER, Reder LM (2004) The effect of midazolam on visual search: implications for understanding amnesia. Proc Natl Acad Sci 101(51):17879–17883PubMedCrossRefGoogle Scholar
  52. Prabhakaran V, Narayanan K, Zhao Z, Gabrieli JDE (2000) Integration of diverse information in working memory within the frontal lobe. Nat Neurosci 3:85–90PubMedCrossRefGoogle Scholar
  53. Reder LM, Oates JM, Thornton ER, Quinlan JJ, Kaufer A, Sauer J (2006) Drug induced amnesia hurts recognition, but only for memories that can be unitized. Psychological Science. Psychol Sci 17(7):562–567PubMedCrossRefGoogle Scholar
  54. Reder LM, Oates JM, Dickison D, Anderson JR, Gyulai F, Quinlan JJ, Ferris JL, Dulik M Jefferson B (in press) Retrograde facilitation under midazolam: the role of general and specific interference. Psychon Bull RevGoogle Scholar
  55. Rich JB, Svoboda E, Brown GG (2006) Diazepam-induced prospective memory impairment and its relation to retrospective memory, attention, and arousal. Hum Psychopharmacol 21:101–108PubMedCrossRefGoogle Scholar
  56. Ryan JD, Cohen NJ (2003) The contribution of long-term memory and the role of frontal-lobe systems in on-line processing. Behav Brain Sci 26(6):756CrossRefGoogle Scholar
  57. Ryan JD, Cohen NJ (2004) Processing and short-term retention of relational information in amnesia. Neuropsychologia 42(4):497–511PubMedCrossRefGoogle Scholar
  58. Ryan JD, Althoff RR, Whitlow S, Cohen NJ (2000) Amnesia is a deficit in relational memory. Psychol Sci 11:454–461PubMedCrossRefGoogle Scholar
  59. Smith MT, Eadie MJ, O’Rourke Brophy T (1981) The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol 19:271–278PubMedCrossRefGoogle Scholar
  60. Turner ML, Engle RW (1989) Working memory capacity: an individual differences approach. J Mem Lang 28:1–28CrossRefGoogle Scholar
  61. Vidailhet P, Danion JM, Kauffmann-Muller F et al (1994) Lorazepam and diazepam effects on memory acquisition in priming tasks. Psychopharmacology 115:397–406PubMedCrossRefGoogle Scholar
  62. Yuill N, Oakhill J, Parkin A (1989) Working memory, comprehension ability and the resolution of text anomaly. Br J Psychol 80(Pt 3):351–361PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Lynne M. Reder
    • 1
  • Iain Proctor
    • 1
  • John R. Anderson
    • 1
  • Ferenc Gyulai
    • 2
  • Joseph J. Quinlan
    • 2
  • Joyce M. Oates
    • 1
  1. 1.Psychology DepartmentCarnegie Mellon UniversityPittsburghUSA
  2. 2.Department of AnesthesiaUniversity of PittsburghPittsburghUSA

Personalised recommendations