Psychopharmacology

, Volume 202, Issue 1–3, pp 67–78

The effects of psychotomimetic and putative cognitive-enhancing drugs on the performance of a n-back working memory task in rats

Original Investigation

Abstract

Rationale

Working memory impairment is a core symptom of schizophrenia, but no existing treatment remediates this deficit. Inconsistent conceptualizations and few reliable translational measures are major hindrances to understanding the neurobiology of this aspect of cognition. Using comparable task designs may help bridge clinical and preclinical research efforts.

Objective

A novel rodent procedure was designed to translate the n-back working memory task used in schizophrenic patients.

Materials and methods

Rats were trained in five-lever operant chambers to recall either the last (one-back) or penultimate (two-back) lever from random sequences of lever presentations of variable lengths. Psychotomimetic doses of amphetamine, dizocilpine maleate (MK801), and (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) were tested for disruption of accuracy, and cognitive-enhancing doses of amphetamine, nicotine, and (±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393 hydrochloride) were examined for improvements in performance.

Results

High doses of amphetamine (0.8 and 1.6 mg/kg) significantly reduced accuracy while increasing total trials; 0.1 mg/kg MK801 and 2.0 mg/kg DOI also reduced accuracy, but the latter concurrently impaired responding. At the lowest dose (0.2 mg/kg), amphetamine increased total trials and rewards without affecting accuracy; 1.0 mg/kg nicotine reduced accuracy without affecting total trials, whereas 10.0 mg/kg SKF38393 had the opposite effect.

Discussion

Although the possibility for mediating behaviors may exist, the rodent n-back task provides a clinically relevant model of working memory. Amphetamine and MK801 produced selective impairments without disrupting responding. The cognitive enhancers did not improve working memory, but low doses of amphetamine improved response efficiency. This novel procedure may be useful for examining cognitive deficits and their potential reversal in animal models of schizophrenia.

Keywords

Amphetamine MK801 Translational Nicotine SKF38393 Schizophrenia 

References

  1. Amico F, Spowart-Mannig L, Anwyl R, Rowan MJ (2007) Performance- and task-dependent effects of the dopamine D1/D5 receptor agonist SKF 38393 on learning and memory in the rat. Eur J Pharmacol 577:71–77PubMedCrossRefGoogle Scholar
  2. Aultman JM, Moghaddam B (2001) Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Psychopharmacology 153:353–364PubMedCrossRefGoogle Scholar
  3. Baddeley AD, Hitch G (1974) Working memory. In: Bower GH (ed) The psychology of learning and motivation. vol. 8. Academic, New York, pp 47–90Google Scholar
  4. Barch DM, Carter CS (2005) Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res 77:43–58PubMedCrossRefGoogle Scholar
  5. Buchanan RW, Davis M, Goff D, Green MF, Keefe RSE, Leon AC, Nuechterlein KH, Laughren T, Levin R, Stover E, Fenton W, Marder SR (2005) A summary of the FDA-NIMH-MATRICS workshop on clinical trials design for neurocognitive drugs for schizophrenia. Schizophr Bull 31:5–19PubMedCrossRefGoogle Scholar
  6. Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA (2007) Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 33:1120–1130PubMedCrossRefGoogle Scholar
  7. Bushnell PJ, Levin ED (1993) Effects of dopaminergic drugs on working and reference memory in rats. Pharmacol Biochem Behav 45:765–76PubMedCrossRefGoogle Scholar
  8. Callicott JH, Mattay VS, Bertolino A et al (1999) Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex 9:20–26PubMedCrossRefGoogle Scholar
  9. Castner SA, Goldman-Rakic PS (2004) Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation. J Neurosci 24:1446–1450PubMedCrossRefGoogle Scholar
  10. Cole BJ, Klewer M, Jones GH, Stephens DN (1993) Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK-801 on performance of an operant delayed matching to position task in rats. Psychopharmacology (Berl) 111:465–471CrossRefGoogle Scholar
  11. Conway ARA, Kane MJ, Bunting MF, Hambrick DZ, Wilhelm O, Engle RW (2005) Working memory span tasks: a methodological review and user’s guide. Psychon Bull Rev 12:769–786PubMedGoogle Scholar
  12. Cowan N (1988) Evolving conceptions of memory storage, selective attention, and their mutual constraints within the human information-processing system. Psychol Bull 104:163–191PubMedCrossRefGoogle Scholar
  13. Cowan N (1999) An embedded-processes model of working memory. In: Miyake A, Shah P (eds) Models of working memory: mechanisms of active maintenance and executive control. Cambridge University Press, New York, pp 62–101Google Scholar
  14. Dunnett SB (1985) Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats. Psychopharmacology (Berl) 87:357–363CrossRefGoogle Scholar
  15. Dunnett SB, Evenden JL, Iversen SD (1988) Delay-dependent short-term memory deficits in aged rats. Psychopharmacology (Berl) 96:174–180CrossRefGoogle Scholar
  16. Engle RW, Conway ARA, Tuholski SW, Shisler RJ (1995) A resource account of inhibition. Psychol Sci 6:122–125CrossRefGoogle Scholar
  17. Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321–330PubMedGoogle Scholar
  18. Green MF, Kern RS, Heaton RK (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 71:41–51CrossRefGoogle Scholar
  19. Goldman-Rakic PS (1994) Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci 6:348–357PubMedGoogle Scholar
  20. Gutnikov SA, Barnes JC, Rawlins JN (1994) Working memory tasks in five-choice operant chambers: use of relative and absolute spatial memories. Behav Neurosci 108:899–910PubMedCrossRefGoogle Scholar
  21. Harper DN, Wisnewski R, Hunt M, Schenk S (2005) (+/−)3,4-methylenedioxymethamphetamine, d-amphetamine, and cocaine impair delayed matching-to-sample performance by an increase in susceptibility to proactive interference. Behav Neurosci 119:455–463PubMedCrossRefGoogle Scholar
  22. Honig WK (1978) Studies of working memory in the pigeon. In: Hulse SH, Fowler H, Honig WK (eds) Cognitive processes in animal behavior. Erlbaum, Hillsdale, NJ, pp 211–247Google Scholar
  23. Kasper S, Resinger E (2003) Cognitive effects and antipsychotic treatment. Psychoneuroendocrinology 28(Suppl 1):27–38PubMedCrossRefGoogle Scholar
  24. Kesner RP, Bierley RA, Pebbles P (1981) Short-term memory: the role of amphetamine. Pharmacol Biochem Behav 15:673–676PubMedCrossRefGoogle Scholar
  25. Levin ED, Simon BB (1998) Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 138:217–230PubMedCrossRefGoogle Scholar
  26. Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR, Berman KF (2005) Regionally specific disturbance of dorsolateral prefrontal–hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 62:379–386PubMedCrossRefGoogle Scholar
  27. Miyake A, Shah P (1999) Toward unified theories of working memory. In: Miyake A, Shah P (eds) Models of working memory: mechanisms of active maintenance and executive control. Cambridge University Press, New York, pp 28–61Google Scholar
  28. Olton DS (1978) Characteristics of spatial memory. In: Hulse SH, Fowler H, Honig WK (eds) Cognitive processes in animal behavior. Erlbaum, Hillsdale, NJ, pp 341–371Google Scholar
  29. Park S, Knopick C, McGurk S, Meltzer HY (2000) Nicotine impairs spatial working memory while leaving spatial attention intact. Neuropsychopharmacology 22:200–209PubMedCrossRefGoogle Scholar
  30. Robinson JK, Mao J-B (1997) Differential effects on delayed non-matching-to-position in rats of microinjections of muscarinic receptor antagonist scopolamine or NMDA receptor antagonist MK-801 into the dorsal or ventral extent of the hippocampus. Brain Res 765:51–60PubMedCrossRefGoogle Scholar
  31. Rogers DC, Wright PW, Roberts JC, Reavill C, Rothaul AL, Hunter AJ (1992) Photothrombotic lesions of the frontal cortex impair the performance of the delayed non-matching to position task by rats. Behav Brain Res 49:231–235PubMedCrossRefGoogle Scholar
  32. Yerkes RM, Dodson JD (1908) The relationship of strength of stimulus to rapidity of habit formation. J Comp Neurol Psychol 18:459–482CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of PsychologyUniversity of DelawareNewarkUSA
  2. 2.CNS DiscoveryAstraZeneca R & D WilmingtonWilmingtonUSA

Personalised recommendations