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Theα 2 antagonist idazoxan remediates certain attentional and executive dysfunction in patients with dementia of frontal type

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Abstract

The mixedα 1/α 2 adrenoceptor agonist clonidine has been shown by us previously to impair certain attentional and executive functions in healthy volunteers. The present investigation examines the effects of theα 2 adrenoceptor antagonist idazoxan (IDZ) on cognitive function in patients with dementia of frontal type (DFT). Using a placebo-controlled ABBA design, three DFT patients were given two doses of IDZ and tested on a range of computerised tests of attention, memory and executive function. Idazoxan was found to produce dose-dependent improvements in performance, particularly on tests of planning, sustained attention, verbal fluency and episodic memory. In contrast, IDZ produced deficits in performance on a test of spatial working memory. These results suggest that IDZ may be useful as a putative cognitive enhancer, particularly in patients showing a specific pattern of frontal lobe dysfunction.

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References

  • Abraham WC, Delanoy RL, Dunn AJ, Zornetzer SF (1979) Locus coeruleus stimulation decreases deoxyglucose uptake in ipsilateral cerebral cortex. Brain Res 172:387–392

    Article  PubMed  Google Scholar 

  • Arnsten AFT, Cai JX (1994) Postsynaptic alpha-2 receptor stimulation improves memory in aged monkeys: indirect effects of yohimbine versus direct effects of clonidine. Neurobiol Aging 14:597–603

    Article  Google Scholar 

  • Arnsten AFT, Goldman-Rakic PS (1985) Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276

    PubMed  Google Scholar 

  • Aston-Jones G, Chiang C, Alexinsky T (1991) Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggest a role in vigilance. In: Barnes CD, Pompeiano O (eds) Progress in brain research, vol. 88. Elsevier Science Publishers, Amsterdam, pp 501–520

    Google Scholar 

  • Baddeley A (1986) Working memory. Oxford University Press, Oxford

    Google Scholar 

  • Beckett PJ, Finch L (1982) Theα 1 andα 2-adrenoceptor involvement in the central cardiovascular action of clonidine in the conscious renal hypertensive cat. Eur J Pharmacol 82:155–160

    Article  PubMed  Google Scholar 

  • Benton AL (1968) Differential effects of frontal lobe disease. Neuropsychologia 6:53–60

    Article  Google Scholar 

  • Bricca G, Dontenwill M, Molines A, Feldman J, Belcourt A, Bousquet P (1989) The imidazoline preferring receptor: binding studies in bovine, rat and human brainstem. Eur J Pharmacol 162:1–9

    Article  PubMed  Google Scholar 

  • Cohen RM, Semple WE, Gross M, Holcomb HJ, Dowling S, Nordahl TE (1988) Functional localization of sustained attention. Neuropsychiat Neuropsychol Behav Neurol 1:3–20

    Google Scholar 

  • Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995a) Contrasting effects of clonidine and diazepam on tests of working memory and planning. Psychopharmacology 120:311–321

    PubMed  Google Scholar 

  • Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995b) Clonidine and diazepam have differential effects on tests of attention and learning. Psychopharmacology 120:322–332

    PubMed  Google Scholar 

  • Davies DR, Parasuraman R (1982) The Psychology of vigilance. Academic Press, London

    Google Scholar 

  • Dennis T, L'Heureux R, Carter C, Scatton B (1987) Pre-synapticα 2-adrenoceptors play a major role in the effects of idazoxan on cortical noradrenaline (as measured by in vivo dialysis) in the rat. J Pharmacol Exp Ther 241:642–649

    PubMed  Google Scholar 

  • De Vos H, Bricca G, De Keyser J, De Backer JP, Bousquet P, Vauquelin G (1994) Imidazoline receptors, non-adrenergic idazoxan binding sites and alpha-2 adrenoceptors in the human central nevous system. Neuroscience 59:589–598

    Article  PubMed  Google Scholar 

  • Downes JJ, Roberts AC, Sahakian BJ, Evenden JL, Morris RG, Robbins TW (1989) Impaired extradimensional shift performance in medicated and unmedicated Parkinson's disease: evidence for a specific attentional dysfunction. Neuropsychologia 27:1329–1344

    Article  PubMed  Google Scholar 

  • Doxey JC, Roach AG, Smith CFC (1983) Studies on RX781094. A selective and specific antagonist ofα 2 adrenoceptors. Br J Pharmacol 78:489–505

    PubMed  Google Scholar 

  • Elfgren C, Passant U, Risberg J (1993) Neuropsychological findings in frontal lobe dementia. Dementia 4:214–219

    PubMed  Google Scholar 

  • Fields RB, van Kammen DP, Peters JL, Rosen J, Van Kammen WB, Nugent A, Stipetic M, Linnoila M (1988) Clonidine improves memory function in schizophrenia independently from change in psychosis: preliminary findings. Schizophr Res 1:417–423

    Article  PubMed  Google Scholar 

  • Folstein MF, Folstein SE, McHugh PR (1975) “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  PubMed  Google Scholar 

  • Francis PT, Holmes C, Webster MT, Stratmann GC, Procter AW, Bowen DM (1993) Preliminary neurochemical findings in non-Alzheimer dementia due to lobar atrophy. Dementia 4:172–177

    PubMed  Google Scholar 

  • Friedland RP, Koss E, Lerner A, Hedera P, Ellis W, Dronkers N, Ober BA, Jagust WJ (1993) Functional imaging, the frontal lobes and dementia. Dementia 4:192–203

    PubMed  Google Scholar 

  • Frith CD (1987) The positive and negative symptoms of schizophrenia reflect impairments in the perception and initiation of action. Psychol Med 17:631–648

    PubMed  Google Scholar 

  • Gallagher M, Kapp BS, Musty RE, Driscoll PA (1977) Memory formation: evidence for a specific neurochemical system in the amygdala. Science 198:423–425

    PubMed  Google Scholar 

  • Glue P, Wilson S, Lawson C, Campling GM, Franklin M, Cowen PJ, Nutt DJ (1991) Acute and chronic idazoxan in normal volunteers: biochemical, physiological and psychological effects. J Psychopharmacol 5:396–403

    Google Scholar 

  • Gregory CA, Hodges JR (1993) Dementia of frontal type and the focal lobar atrophies. Int Rev Psychiatry 5:397–406

    Google Scholar 

  • Gustafson L (1993) Clinical picture of frontal lobe degeneration of non-Alzheimer type. Dementia 4:143–148

    PubMed  Google Scholar 

  • Jones GMM, Sahakian BJ, Levy R, Warburton DM, Gray JA (1992) Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer's disease. Psychopharmacology 108:485–494

    Article  PubMed  Google Scholar 

  • Krystal JH, McDougle CJ, Woods SW, Price LH, Heninger GR, Charney DS (1992) Dose-response relationships for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine. Psychopharmacology 108:313–319

    Article  PubMed  Google Scholar 

  • Langer SZ, Cavero I, Massinham R (1980) Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. Hypertension 2:372–382

    PubMed  Google Scholar 

  • Liddle PF (1987) Schizophrenic syndromes, cognitive performance and neurological dysfunction. Psychol Med 17:49–57

    PubMed  Google Scholar 

  • Litman RE, Hong WW, Weissman EM, Su T-P, Potter WZ, Pickar D (1993) Idazoxan, anα 2 antagonist, augments fluphenazine in schizophrenic patients: a pilot study. J Clin Psychopharmacol 13:264–267

    PubMed  Google Scholar 

  • McNicol D (1972) A primer of signal detection theory. George Allen and Unwin, London

    Google Scholar 

  • Mair RG, McEntee WJ (1986) Cognitive enhancement in Korsakoff's pyschosis by clonidine: a comparison withl-dopa and ephedrine.Psychopharmacology 88:374–380

    Article  PubMed  Google Scholar 

  • Middleton HC, Coull JT, Sahakian BJ, Robbins TW (1994) Clonidine-induced changes in the spectral distribution of heart-rate variability correlate with performance on a test of sustained attention. J Psychopharmacol 8:1–7

    Google Scholar 

  • Milner B (1964) Some effects of frontal lobectomy in man. In: Warren JM, Akert K (eds) The frontal granular crotex and behaviour. McGraw-Hill, New York, pp 313–331

    Google Scholar 

  • Neary D (1989) Non-Alzheimer dementia. Curr Opin Neurol Neurosurg 2:457–459

    Google Scholar 

  • Neary D, Snowden JS, Northern B, Goulding PJ (1988) Dementia of frontal lobe type. J Neurol Neurosurg Psychiatry 51:353–361

    PubMed  Google Scholar 

  • Nelson HE (1982) National adult reading test manual. NFER-Nelson, Windsor, Berks

    Google Scholar 

  • Orrell MW, Sahakian BJ (1991) Dementia of frontal lobe type. Psychol Med 21:553–556

    PubMed  Google Scholar 

  • Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW (1990) Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 29:993–1006

    Article  Google Scholar 

  • Owen AM, Morris RG, Sahakian BJ, Polkey CE, Robbins TW (1995a) Double dissociations of memory and executive functions in working memory tasks following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man. Brain (in press)

  • Owen AM, Sahakian BJ, Semple J, Polkey CE, Robbins TW (1995b) Visuo-spatial short-term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia 33:1–24

    Article  PubMed  Google Scholar 

  • Robbins TW (1984) Cortical noradrenaline, attention and arousal. Psychol Med 14:13–21

    PubMed  Google Scholar 

  • Sahakian BJ, Joyce E, Lishman WA (1987) Cholinergic effects on constructional abilities and on mnemonic processes: a case report. Psychol Med 17:329–333

    PubMed  Google Scholar 

  • Sahakian BJ, Morris RGM, 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 111:695–718

    PubMed  Google Scholar 

  • Sahakian BJ, Jones GMM, Levy R, Gray JA, Warburton DM (1989) The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type Br J Psychiatry 154:797–800

    PubMed  Google Scholar 

  • Sahakian BJ, Owen AM, Morant NJ, Eagger SA, Boddington S, Crayton L, Crockford HA, Crooks M, Levy R (1993) Further analysis of the cognitive effects of tetrahydroaminoacradine (THA) in Alzheimer's disease: assessment of attentional and mnemonic function using CANTAB. Psychopharmacology: 110:395–401

    Article  PubMed  Google Scholar 

  • Sahgal A (1987) Some limitations of indices derived from signal detection theory: evaluation of an alternative index for measuring bias in memory tasks. Psychopharmacology 91:517–520

    Google Scholar 

  • Sahgal A, Sahakian BJ, Robbins TW, Wray CJ, Lloyd S, Cook JH, McKeith IG, Disley JCA, Eagger S, Boddington S, Edwardson JA (1991) Detection of visual memory and learning deficits in Alzheimer's disease using the Cambridge Neuropsychological Test Automated Battery. Dementia 2:150–158

    Google Scholar 

  • Schmidt M, Matochik J, Risinger R, Zametkin A, Schouten J, Cohen R, Potter W (1994) Effects of idazoxan on regional brain metabolism. Abstract for American Society for Clinical Pharma-cology and Therapeutics, Spring meeting

  • Shallice T (1982) Specific impairments in planning. Philos Trans R Soc Lond B298:199–209

    Google Scholar 

  • Smith AP, Wilson SJ, Glue P, Nutt DJ (1992) The effects and after effects of theα 2-adrenoceptor antagonist idazoxan on mood, memory and attention in normal volunteers. J Psychopharmacol 6:376–381

    Google Scholar 

  • Stein L, Belluzzi JD, Wise CD (1975) Memory enhancement by central administration of norepinephrine. Brain Res 84:329–335

    Article  PubMed  Google Scholar 

  • Sunderland T, Tariot PN, Mueller EA, Murphy DL, Weingartner H, Cohen RM (1985) Cognitive and behavioural sensitivity to scopolamine in Alzheimer patients and controls. Psychopharmacol Bull 21:676–679

    PubMed  Google Scholar 

  • Sunderland T, Tario PN, Weingartner H, Murphy DL, Newhouse PA, Mueller EA, Cohen RM (1986) Pharmacological modelling of Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 10:599–619

    Article  PubMed  Google Scholar 

  • Trenerry MR, Jack CR, Ivnik RJ, Sharbrough FW, Cascino GD, Hirschorn KA, Marsh WR, Kelly PJ, Meyer FB (1993) MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurology 43:1800–1805

    PubMed  Google Scholar 

  • Troster AI, Butters N, Salmon DP, Cullum CM, Jacobs D, Brandt J, White RF (1993) The diagnostic utility of savings scores: differentiating Alzheimer's and Huntington's disease with the logical memory and visual reproduction tests. J Clin Exp Neuropsychol 15:773–788

    PubMed  Google Scholar 

  • Wechsler D (1955) Wechsler adult intelligence scale. The Psychological Corporation, New York

    Google Scholar 

  • Wechsler D (1987) Wechsler memory scale—revised. The Psychological Corporation, Harcourt Brace Jovanovich, New York

    Google Scholar 

  • Wesnes K, Warburton DM (1984) Effects of scopolamine and nicotine on human rapid information processing performance. Psychopharmacology 82:147–150

    Article  PubMed  Google Scholar 

  • Wilkins AJ, Shallice T, McCarthy R (1987) Frontal lesions and sustained attention. Neuropsychologia 25:359–365

    Article  PubMed  Google Scholar 

  • Wilson B, Cockburn J, Baddeley AD (1985) Rivermead behavioural memory test. Thames Valley Test, Titchfield, Fareham

    Google Scholar 

  • Woods DL, Knight RT (1986) Electrophysiologic evidence of increased distractability after dorsolateral prefrontal lesions. Neurology 36:212–216

    PubMed  Google Scholar 

  • Woods SW, Hoffer PB, McDougle CJ, Krystal JH, Heninger GR, Charney DS (1991) Effects of yohimbine on regional cerebral blood flow in panic disorder. Soc Neurosci Abstr 17:293.8

    Google Scholar 

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  1. J. T. Coull

    Present address: Wellcome Department of Cognitive Neurology, Institute of Neurology, Queen Sq., WC1N 3BG, London, UK

Authors and Affiliations

  1. Department of Experimental Psychology, University of Cambridge, Downing Street, CB2 3EB, Cambridge, UK

    J. T. Coull

  2. Department of Psychiatry, University of Cambridge Clinical School, Addenbrooke's Hospital, Hills Road, CB2 2QQ, Cambridge, UK

    B. J. Sahakian

  3. University Neurology Unit, Addenbrooke's Hospital, Hills Road, CB2 2QQ, Cambridge, UK

    J. R. Hodges

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  2. B. J. Sahakian
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  3. J. R. Hodges
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Coull, J.T., Sahakian, B.J. & Hodges, J.R. Theα 2 antagonist idazoxan remediates certain attentional and executive dysfunction in patients with dementia of frontal type. Psychopharmacology 123, 239–249 (1996). https://doi.org/10.1007/BF02246578

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  • DOI: https://doi.org/10.1007/BF02246578

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