, Volume 120, Issue 3, pp 311–321 | Cite as

Contrasting effects of clonidine and diazepam on tests of working memory and planning

  • J. T. Coull
  • H. C. Middleton
  • T. W. Robbins
  • B. J. Sahakian
Original Investigation


Theα2 adrenoceptor has recently been implicated in working memory (WM), a function dependent on the integrity of the prefrontal cortex. Using a double-blind, placebo-controlled design, the present investigation examines the effects of two doses (1.5 µg/kg and 2.5 µg/kg) of the mixedα1/α2 adrenoceptor agonist clonidine (CLO) on performance of various computerised tests of WM and planning in healthy, young volunteers. These are compared to the effects produced by two doses (5 mg and 10 mg) of diazepam (DZP) on largely the same set of neuropsychological tests in a comparable set of subjects. Administration of CLO resulted in impulsivity of responding in a planning task, as well as differential dose-dependent effects on two analogous tests of spatial and visual WM. The nature of these effects were suggestive of mnemonic, rather than executive, dysfunction. Conversely, DZP produced specific deficits on tests of spatial WM and planning very similar to those seen following lesions to the frontal lobes. Therefore, these two sedative drugs produce doubly dissociable, dose-dependent effects on different aspects of cognitive function.

Key words

α2 Adrenoceptor Benzodiazepine Frontal cortex Executive function 


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  1. Angel A (1993) Central neuronal pathways and the process of anaestheisa. Br J Anaesth 71:148–163PubMedGoogle Scholar
  2. Arnsten AFT, Contant TA (1992) Alpha-2 adrenergic agonists decrease distractability in aged monkeys performing the delayed response task. Psychopharmacology 108:159–169CrossRefPubMedGoogle Scholar
  3. Arnsten AFT, Goldman-Rakic PS (1985) Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276PubMedGoogle Scholar
  4. Arnsten AFT, Cai JX, Goldman-Rakic PS (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side-effects. J Neurosci 8:4287–4298PubMedGoogle Scholar
  5. Baddeley A (1986) Working memory. Clarednon Press, OxfordGoogle Scholar
  6. Brozoski TJ, Brown R, Rosvold HF, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkeys. Science 205:929–931PubMedGoogle Scholar
  7. Charney DS, Heninger GR (1986) Abnormal regulation of noradrenergic function in panic disorder. Am J Psychiatry 43:1042–1054Google Scholar
  8. Clark CR, Geffen GM, Geffen LB (1989) Catecholamines and the covert orientation of attention in humans. Neuropsychologia 27:131–139CrossRefPubMedGoogle Scholar
  9. Cochran WG, Cox GM (1957) Experimental designs. Wiley, New York, pp 127–131Google Scholar
  10. Coull JT (1994) Monoaminergic modulation of human attentional and executive function. PhD thesis, University of CambridgeGoogle Scholar
  11. Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995) Clonidine and diazepam have differential effects on tests of attention and learning. Psychopharmacology (in press).Google Scholar
  12. Curran HV (1991) Benzodiazepines, memory and mood: a review. Psychopharmacology 105:1–8PubMedGoogle Scholar
  13. Curran HV, Schifano F, Lader M (1991) Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory, psychomotor performance and mood. Psychopharmacology 103:83–90CrossRefPubMedGoogle Scholar
  14. Dollery CT, Davies DS, Draffan GH, Dargie HJ, Dean CR, Reid JL, Clare RA, Murray S (1976) Clinical pharmacology and pharmacokinetics of clonidine. Clin Pharmacol Ther 19:11–18PubMedGoogle Scholar
  15. Doze VA, Chen BX, Maze M (1989) Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of centralα 2 adrenoceptors. Anesthesiology 71:75–79PubMedGoogle Scholar
  16. Frith CD, Dowdy J, Ferrier IN, Crow TJ (1985) Selective impairment of paired associated learning after administration of a centrally-acting adrenergic agonist (clonidine). Psychopharmacology 87:490–493CrossRefPubMedGoogle Scholar
  17. Goldman-Rakic PS (1987) Circuitry of the primate prefrontal cortex and the regulation of behaviour by representational memory. In: Plum F (ed) Handbook of physiology: the neurons system of the brain, higher functions of the brain, section 1, vol. V, part 1. American Physiological Soceity, Bethesda, Md.Google Scholar
  18. Goldman-Rakic PS, Lidow MS, Gallager DW (1990) Overlap of dopaminergic adrenergic and serotonergic receptors and complementarity of their subtypes of primate prefrontal cortex. J Neurosci 10:2125–2138PubMedGoogle Scholar
  19. Hills M, Armitage P (1979) The two-period cross-over clinical trial. Br J Clin Pharmacol 8:7–20PubMedGoogle Scholar
  20. Johnson LC, Chernik DA (1982) Sedative-hypnotics and human performance. Psychopharmacology 76:101–113CrossRefPubMedGoogle Scholar
  21. Luciana M, Depue RA, Arbisi P, Leon A (1992) Facilitation of working memory in humans by a D2 dopamine receptor agonist. J Cog Neurosci 4:58–68Google Scholar
  22. Morris RG, Ahmed S, Syed GM, Toone BK (1993) Neural correlates of planning ability: frontal lobe activation during the Tower of London test. Neuropsychologia 31:1367–1378PubMedGoogle Scholar
  23. Nelson HE (1982) National adult reading test manual. NFER-Nelson, Windsor, BerksGoogle Scholar
  24. Norman DA, Shallice T (1986) Attention to action: willed and automatic control of behaviour. In: Davidson RJ, Schwarts GE, Shapiro D (eds) Cousciousness and self-regulation, advances in research theory, vol. 4. Plenum Press, New York, pp 1–18Google Scholar
  25. Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW (1990) Planning and spatial working memory following frontal lobe lesions in Man. Neuropsychologia 29:993–100Google Scholar
  26. Owen AM, Roberts AC, Polkey CE, Sahakian BJ, Robbins TW (1991) Extradimensional versus intradimensional set-shifting performance following frontal lobe excisions, temporal lobe excision or amygdalo-hippocampectomy in man. Neuropsychologia 29:993–1006CrossRefPubMedGoogle Scholar
  27. Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP, Lange KW, Robbins TW (1992) Fronto-striatal cognitive deficits at different stages of Parkinson's disease. Brain 115:1727–1751PubMedGoogle Scholar
  28. Owen AM, Sahakian BJ, Hodges JR, Summers BA, Polkey CE, Robbins TW (1995a) Dopatime-dependent fronto-striatal planning deficits in early Parkinson's disease. Neuropsychology (in press)Google Scholar
  29. Owen AM, Morris RG, Sahakian BJ, Polkey CE, Robbins TW (1995b) Double dissociation of memory and executive functions in working memory tasks following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man. Brain (in press)Google Scholar
  30. Petrides M (1991) Monitoring of selections of visual stimuli and the primate frontal cortex. Proc R Soc Lond B 246:293–298Google Scholar
  31. Petrides M, Milner B (1982) Deficits on subject-ordered tasks after frontal and temporal-lobe lesions in man. Neuropsychologia 20:249–262CrossRefPubMedGoogle Scholar
  32. Posner MI, Walker JA, Friedrich FJ, Rafal RD (1984) Effects of parietal injury in covert orienting of attention. J Neurosci 4:1863–1874PubMedGoogle Scholar
  33. Robbins TW, James M, Owen AM, Sahakian BJ, McInnes L, Rabbitt P (1994) Cambridge Neuropsychological Test Automated Test Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5:266–281PubMedGoogle Scholar
  34. Rusted JM, Eaton-Williams, Warburton DM (1991) A comparison of the effects of scopolamine and diazepam on working memory. Psychopharmacology 105:442–445CrossRefPubMedGoogle Scholar
  35. Sahakian BJ, Owen AM (1992) Computerised assessment in neuropsychiatry using CANTAB. J R Soc Med 85:399–402PubMedGoogle Scholar
  36. Sawaguchi T, Goldman-Rakic PS (1994) The role of D1-dopamine receptor in working memory. Local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysio 71:515–528Google Scholar
  37. Shallice T (1982) Specific impairments in planning. Philos Trans R Soc Lond B298:199–209Google Scholar
  38. Shallice T (1988) From Neuropsychology to mental structure. Cambridge University Press, CambridgeGoogle Scholar
  39. Stuss DT, Benson DF (1986) The frontal lobes. Raven Press, New YorkGoogle Scholar
  40. Wilson FAW, Scalaidhe SP, Goldman-Rakic PS (1993) Dissociation of object and spatial procesing domains in primate prefrontal cortex. Science 260:1955–1958PubMedGoogle Scholar
  41. Winer BJ (1974) Statistical principles in experimental design. McGraw-Hill, New YorkGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • J. T. Coull
    • 1
  • H. C. Middleton
    • 2
  • T. W. Robbins
    • 1
  • B. J. Sahakian
    • 2
  1. 1.Department of Experimental PsychologyUniversity of CambridgeCambridgeUK
  2. 2.Department of PsychiatryUniversity of Cambridge Clinical School, Addenbrooke's HospitalCambridgeUK

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