Abstract
Rationale
In recent years, there has been a growing interest in the role of dopamine (DA) both in the pathogenesis of unipolar depression and in motivated behaviour. The innovative technique of acute tyrosine depletion presents an opportunity to characterise further its function in these domains.
Objective
The present study examined the physiological, subjective and cognitive effects of acute tyrosine depletion in healthy volunteers.
Methods
A double-blind, placebo-controlled, parallel group design was employed. Half of the participants ingested a balanced amino-acid mixture (BAL) and the other half received an identical mixture except that tyrosine and phenylalanine were absent (TYR-free). Plasma amino acid concentrations and subjective ratings were monitored at both baseline (T0) and 5 h following consumption (T5) of the mixtures. A comprehensive neuropsychological test battery was also administered at T5.
Results
Relative to the BAL group, the reduction in TYR availability to the brain was more marked in the TYR-free group. Employment of psychological rating scales revealed that, compared with the BAL group, the TYR-free group became less content and more apathetic. For the affective go/no-go task, whilst the BAL group exhibited a happy latency bias, the TYR-free group demonstrated a sad latency bias. Furthermore, in the decision-making task, the rate at which the TYR-free group increased their bets in response to more likely outcomes was lower than that of the BAL group. Taken together, these neuropsychological findings strikingly paralleled those reported in previous investigations of unipolar depression. The experimental groups could not be differentiated on any of the other neuropsychological measures, including more classical assessments of fronto-executive function.
Conclusion
These findings are consistent with the hypothesis that dopaminergic factors are particularly involved in disrupted affect/reward-based processing characteristic of clinical depression.
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References
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington
Baker SC, Rogers RD, Owen AM, Frith CD, Dolan RJ, Frackowiak RSJ, Robbins TW (1996) Neural systems engaged by planning: a PET study of the tower of London task. Neuropsychologia 34:515–526
Beauregard M, Chertkow H, Bub H, Murtha S, Dixon R, Evans A (1997) The neural substrate for concrete, abstract, and emotional word lexical: a positron emission tomography study. J Cogn Neurosci 9:441–461
Bechara A, Damasio AR, Damasio H, Anderson SW (1994) Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50:7–15
Bechara A, Tranel D, Damasio H, Damasio AR (1996) Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cereb Cortex 6:215–225
Bechara A, Damasio H, Tranel D, Damasio AR (1997) Deciding advantageously before knowing the advantageous strategy. Science 275:1293–1294
Bechara A, Damasio H, Tranel D, Anderson SW (1998) Dissociation of working memory from decision making within the human prefrontal cortex. J Neurosci 18:428–437
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571
Beck AT, Steer RA, Garbin MG (1988) Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 8:77–100
Biggio G, Porceddu ML, Gessa GL (1976) Decrease of homovanillic, dihydroxyphenylacetic acid and cyclic adenosine-3',5'-monophosphate content in the rat caudate nucleus induced by the acute administration of an amino acid mixture lacking tyrosine and phenylalanine. J Neurochem 26:1253–1255
Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218
Bower GH (1981) Mood and memory. Am Psychol 36:129–148
Browne S, Garavan J, Gervin M, Roe M, Larkin C, O'Callaghan E (1998) Quality of life in schizophrenia: insight and subjective response to neuroleptics. J Nerv Ment Dis 186:74–78
Brozoski TJ, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–932
Coull JT, Sahakian BJ, Middleton HC, Young AH, Park SB, McShane RH, Cowen PJ, Robbins TW (1995) Differential effects of clonidine, haloperidol, diazepam and tryptophan depletion on focused attention and attentional search. Psychopharmacology 121:222–230
Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 47:411–418
Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C (1999) Acute tryptophan depletion in healthy young women with a family history of major affective disorder. Psychol Med 29:35–46
Elliott R, Dolan RJ (1998) The medial prefrontal cortex in depression. In: Ebert D, Ebmeier KP (eds) New models for depression. Karger, Basel, pp 72–93
Elliott R, Sahakian BJ, McKay AP, Herrod JJ, Robbins TW, Paykel ES (1996) Neuropsychological impairments in unipolar depression: the influence of perceived failure on subsequent performance. Psychol Med 26:975–989
Elliott R, Sahakian BJ, Matthews K, Bannerjea A, Rimmer J, Robbins TW (1997) Effects of methylphenidate on spatial working memory and planning in healthy young adults. Psychopharmacology 131:196–206
Elliott R, Rees G, Dolan RJ (1999) Ventromedial prefrontal cortex mediates guessing. Neuropsychologia 37:403–411
Elliott R, Friston KJ, Dolan RJ (2000) Dissociable neural responses in human reward systems. J Neurosci 20:6159–6165
Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ (2002) The neural basis of mood-congruent processing biases in depression. Arch Gen Psychiatry 59:597–604
Furst P, Pollack L, Graser TA, Godel H, Stehle P (1990) Appraisal of four pre-column derivatization methods for the high performance liquid chromatographic determination of free amino acids in biological materials. J Chromatogr 499:557–569
Greenhouse SW, Geisser S (1959) On methods in the analysis of profile data. Psychometrika 24:95–112
Harmer CJ, McTavish SF, Clark L, Goodwin GM, Cowen PJ (2001) Tyrosine depletion attenuates dopamine function in healthy volunteers. Psychopharmacology 154:105–111
Howell DC (1997) Statistical methods for psychology, 4th edn. Duxbury Press, London
Huynh H, Feldt LS (1976) Estimation of the Box correction for degrees of freedom from sample data in the randomised block and split-plot designs. J Educ Stat 1:69–82
Jacobs D, Silverstone T (1986) Dextroamphetamine-induced arousal in human subjects as a model for mania. Psychol Med 16:323–329
Kapur S, Mann JJ (1992) Role of the dopaminergic system in depression. Biol Psychiatry 32:1–17
Kimberg DY, D'Esposito M, Marah MJ (1997) Effects of bromocriptine on human subjects depends on working memory capacity. Neuroreport 8:3581–3585
Koob GF, Nestler EJ (1997) The neurobiology of drug addiction. J Neuropsychiatry Clin Neurosci 9:482–497
Lapin IP, Oxenkrug GF (1969) Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect. Lancet 1:132–136
Leyton M, Ghadirian AM, Young SN, Palmour RM, Blier P, Helmers KF, Benkelfat C (2000a) Depressive relapse following acute tryptophan depletion in patients with major depressive disorder. J Psychopharmacol 14:284–287
Leyton M, Young SN, Pihl RO, Etezadi S, Lauze C, Blier P, Baker GB, Benkelfat C (2000b) Effects on mood of acute phenylalanine/tyrosine depletion in healthy women. Neuropsychopharmacology 22:52–63
Luciana M, Collins PF (1997) Dopaminergic modulation of working memory for spatial but not object cues in normal volunteers. J Cogn Neurosci 9:330–347
Luciana M, Depue RA, Arbisi P, Leon A (1992) Facilitation of working memory in humans by a D2 dopamine receptor agonist. J Cogn Neurosci 4:58–67
Marin RS, Biedrzycki RC, Firinciogullari S (1991) Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res 38:143–162
McAllister TW (2000) Apathy. Semin Clin Neuropsychiatry 5:275–282
McNair DM, Lorr M, Droppleman LF (1992) Manual for the profile of mood states. Educational and Industrial Testing Service, San Diego
McTavish SF, Callado L, Cowen PJ, Sharp T (1999a) Comparison of the effects of alpha-methyl-p-tyrosine and a tyrosine-free amino acid load on extracellular noradrenaline in the rat hippocampus in vivo. J Psychopharmacol 13:379–384
McTavish SF, Cowen PJ, Sharp T (1999b) Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release. Psychopharmacology 141:182–188
McTavish SF, McPherson MH, Sharp T, Cowen PJ (1999c) Attenuation of some subjective effects of amphetamine following tyrosine depletion. J Psychopharmacol 13:144–147
McTavish SF, McPherson MH, Harmer CJ, Clark L, Sharp T, Goodwin GM, Cowen PJ (2001) Antidopaminergic effects of dietary tyrosine depletion in healthy subjects and patients with manic illness. Br J Psychiatry 179:356–360
Mehta MA, Sahakian BJ, McKenna PJ, Robbins TW (1999) Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson's disease. Psychopharmacology 46:162–174
Mehta MA, Swainson R, Ogilvie AD, Sahakian BJ, Robbins TW (2001) Improved short-term spatial memory but impaired reversal learning following the dopamine D2 agonist bromocriptine in human volunteers. Psychopharmacology 159:10–20
Muller U, von Cramon DY, Pollmann S (1998) D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 18:2720–2728
Murphy FC, Sahakian BJ, Rubinsztein JS, Michael A, Rogers RD, Robbins TW, Paykel ES (1999) Emotional bias and inhibitory control processes in mania and depression. Psychol Med 29:1307–1321
Murphy FC, Rubinsztein JS, Michael A, Rogers RD, Robbins TW, Paykel ES, Sahakian BJ (2001) Decision-making cognition in mania and depression. Psychol Med 31:679–693
Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002) The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacology 163:42–53
Naranjo CA, Tremblay LK, Busto UE (2001) The role of the brain reward system in depression. Progr Neuropsychopharmacol Biol Psychiatry 25:781–823
Nelson HE (1982) National adult reading test (NART): test manual. NFER-Nelson, Windsor
Nie NH, Hadlai HC, Jenkins JG, Steinbrenner K, Bent DH (1970) Statistical package for the social sciences. McGraw-Hill, New York
Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 239:94–98
Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW (1990) Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 28:1021–1034
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 115:1727–1751
Owen AM, Roberts AC, Hodges JR, Summers BA, Polkey CE, Robbins TW (1993) Contrasting mechanisms of impaired attentional set-shifting in patients with frontal lobe damage or Parkinson's disease. Brain 116:1159–1175
Owen AM, Sahakian BJ, Hodges JR, Summers BA, Polkey CE, Robbins TW (1995) Dopamine-dependent frontostriatal planning deficits in early Parkinson's disease. Neuropsychology 9:1–15
Owen AM, Evans AC, Petrides M (1996) Evidence for a two-stage model of spatial working memory processing within the lateral frontal cortex: a positron emission tomography study. Cereb Cortex 6:31–38
Pandya DN, Yeterian EH (1996) Morphological correlations of human and monkey frontal lobe. In: Damasio AR, Damasio H, Christen Y (eds) Neurobiology of decision-making. Springer, Berlin Heidelberg New York, pp 13–45
Pardridge WM (1977) Kinetics of competitive inhibition of neutral amino acid transport across the blood–brain barrier. J Neurochem 28:103–108
Park SB, Coull JT, McShane RH, Young AH, Sahakian BJ, Robbins TW, Cowen PJ (1994) Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology 33:575–588
Pluck GC, Brown RG (2002) Apathy in Parkinson's disease. J Neurol Neurosurg Psychiatry 73:636–642
Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM (1999) Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology 141:362–369
Robbins TW (2000) Chemical neuromodulation of fronto-executive functions in humans and other animals. Exp Brain Res 133:130–138
Robbins TW, Everitt BJ (1996) Neurobehavioural mechanisms of reward and motivation. Curr Opin Neurobiol 6:228–236
Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, Baker NB, Hunter J, Carthy T, Booker E, London M, Deakin JF, Sahakian BJ, Robbins TW (1999a) Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology 20:322–339
Rogers RD, Owen AM, Middleton HC, Williams EJ, Pickard JD, Sahakian BJ, Robbins TW (1999b) Choosing between small, likely rewards and large, unlikely rewards activates inferior and orbital prefrontal cortex. J Neurosci 20:9029–9038
Rogers RD, Andrews TC, Grasby PM, Brooks DJ, Robbins TW (2000) Contrasting cortical and subcortical activations produced by attentional-set shifting and reversal learning in humans. J Cogn Neurosci 12:142–162
Rubinsztein JS, Rogers RD, Riedel WJ, Mehta MA, Robbins TW, Sahakian BJ (2001) Acute dietary tryptophan depletion impairs maintenance of "affective set" and delayed visual recognition in healthy volunteers. Psychopharmacology 154:319–326
Sahakian BJ, Morris RG, 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 11:695-718
Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122:509–522
Schultz W (1997) Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol 7:191–197
Sheehan BD, Tharyan P, McTavish SFB, Campling GM, Cowen PJ (1996) Use of a dietary manipulation to deplete plasma tyrosine and phenylalanine in healthy subjects. J Psychopharmacol 10:231–234
Smith KA, Fairburn CG, Cowen PJ (1997) Relapse of depression after rapid depletion of tryptophan. Lancet 349:915–919
Smith SE, Pihl RO, Young SN, Ervin FR (1987) A test of possible cognitive and environmental influences on the mood-lowering effect of tryptophan depletion in normal males. Psychopharmacology 91:451–457
Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG (1992) Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci 4:134–139
Teasdale JD, Howard RJ, Cox SG, Ha Y, Brammer MJ, Williams SCR, Checkley SA (1999) Functional MRI study of the cognitive generation of affect. Am J Psychiatry 156:209–215
Willner P (1983) Dopamine and depression: a review of recent evidence. Brain Res Rev 6:211–246
Wise RA (1989) The brain and reward. In: Liebman JM, Copper SJ (eds) Neuropharmacological basis of reward. Clarendon Press, Oxford, pp 377–424
Acknowledgements
We thank the volunteers for participating and the staff of ward R4 for their assistance and patience. The study was funded by a Wellcome Trust Programme Grant awarded to Professors Trevor Robbins, Barry Everitt and Barbara Sahakian, and Dr. Angela Roberts, and was completed within the MRC Centre for Behavioural and Cognitive Neuroscience. A.M. was supported by a MRC Research Studentship and J.S.R. was the recipient of the Betty Behrens Research Fellowship at Clare Hall, Cambridge, and received a Sackler studentship. We thank Dr. Sarah McTavish for methodological advice and Dr. Mike Franklin and his team for performing the biochemical analyses of the blood samples.
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McLean, A., Rubinsztein, J.S., Robbins, T.W. et al. The effects of tyrosine depletion in normal healthy volunteers: implications for unipolar depression. Psychopharmacology 171, 286–297 (2004). https://doi.org/10.1007/s00213-003-1586-8
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DOI: https://doi.org/10.1007/s00213-003-1586-8