The effects of tyrosine depletion in normal healthy volunteers: implications for unipolar depression
- 451 Downloads
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.
The present study examined the physiological, subjective and cognitive effects of acute tyrosine depletion in healthy volunteers.
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.
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.
These findings are consistent with the hypothesis that dopaminergic factors are particularly involved in disrupted affect/reward-based processing characteristic of clinical depression.
KeywordsTyrosine Depletion Dopamine Neuropsychology Reward Affective processing
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.
- American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, WashingtonGoogle Scholar
- 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 9:441–461Google Scholar
- Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571Google Scholar
- 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 26:1253–1255PubMedGoogle Scholar
- Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218Google Scholar
- Elliott R, Dolan RJ (1998) The medial prefrontal cortex in depression. In: Ebert D, Ebmeier KP (eds) New models for depression. Karger, Basel, pp 72–93Google Scholar
- Greenhouse SW, Geisser S (1959) On methods in the analysis of profile data. Psychometrika 24:95–112Google Scholar
- Howell DC (1997) Statistical methods for psychology, 4th edn. Duxbury Press, LondonGoogle Scholar
- 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 1:69–82Google Scholar
- 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 22:52–63Google Scholar
- Luciana M, Collins PF (1997) Dopaminergic modulation of working memory for spatial but not object cues in normal volunteers. J Cogn Neurosci 9:330–347Google Scholar
- Luciana M, Depue RA, Arbisi P, Leon A (1992) Facilitation of working memory in humans by a D2 dopamine receptor agonist. J Cogn Neurosci 4:58–67Google Scholar
- McNair DM, Lorr M, Droppleman LF (1992) Manual for the profile of mood states. Educational and Industrial Testing Service, San DiegoGoogle Scholar
- 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 13:379–384Google Scholar
- McTavish SF, Cowen PJ, Sharp T (1999b) Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release. Psychopharmacology 141:182–188Google Scholar
- McTavish SF, McPherson MH, Sharp T, Cowen PJ (1999c) Attenuation of some subjective effects of amphetamine following tyrosine depletion. J Psychopharmacol 13:144–147Google Scholar
- 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 159:10–20Google Scholar
- Nelson HE (1982) National adult reading test (NART): test manual. NFER-Nelson, WindsorGoogle Scholar
- Nie NH, Hadlai HC, Jenkins JG, Steinbrenner K, Bent DH (1970) Statistical package for the social sciences. McGraw-Hill, New YorkGoogle Scholar
- Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 239:94–98Google Scholar
- Owen AM, Sahakian BJ, Hodges JR, Summers BA, Polkey CE, Robbins TW (1995) Dopamine-dependent frontostriatal planning deficits in early Parkinson's disease. Neuropsychology 9:1–15Google Scholar
- 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 13–45Google Scholar
- Pardridge WM (1977) Kinetics of competitive inhibition of neutral amino acid transport across the blood–brain barrier. J Neurochem 28:103–108Google Scholar
- 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 20:322–339PubMedGoogle Scholar
- 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 20:9029–9038Google Scholar
- 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 11:695-718Google Scholar
- 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 10:231–234Google Scholar
- Wise RA (1989) The brain and reward. In: Liebman JM, Copper SJ (eds) Neuropharmacological basis of reward. Clarendon Press, Oxford, pp 377–424Google Scholar