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The effects of acute tyrosine and phenylalanine depletion on spatial working memory and planning in healthy volunteers are predicted by changes in striatal dopamine levels

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Abstract

Rationale

Dopamine (DA) is considered important in the modulation of tasks of spatial working memory. However, the findings from studies in humans to date are mixed. While this may be due to the characteristics of the tasks used, it is also possible that these findings are explained by variable central effects of the manipulations used.

Objective

To test the effects of acute tyrosine and phenylalanine depletion (TPD, which reduces synthesis and release of brain DA) on cognitive function and relate changes in performance accuracy to the central effects of TPD measured with [11C]raclopride positron emission tomography (PET).

Methods

Fourteen participants were given tests of spatial working memory, planning, verbal memory span and trial-and-error learning after acute TPD, seven of whom also received PET scans to measure changes in striatal DA levels.

Results

Although TPD produced a clear reduction in tyrosine and phenylalanine availability to the brain, no impairments on any of the cognitive tests were observed. However, changes in spatial working memory and planning accuracy after TPD showed a highly significant relationship with the changes in striatal DA levels.

Conclusions

Our findings suggest that the effects of TPD on spatial working memory and planning may be unreliable due to the variability of the changes in brain DA levels achieved with this manipulation.

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References

  • Alexander GE, Delong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking the basal ganglia and cortex. Annu Rev Neurosci 9:357–381

    Article  PubMed  CAS  Google Scholar 

  • Alexander GE, Crutcher MD, DeLong MR (1990) Basal ganglia–thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 85:119–146

    PubMed  CAS  Google Scholar 

  • Arnsten AF, Cai JX, Steere JC, Goldman-Rakic PS (1995) Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys. J Neurosci 15:3429–3439

    PubMed  CAS  Google Scholar 

  • Baker SC, Frith CD, Frackowiak RS, Dolan RJ (1996a) Active representation of shape and spatial location in man. Cereb Cortex 6:612–619

    Article  PubMed  CAS  Google Scholar 

  • Baker SC, Rogers RD, Owen AM, Frith CD, Dolan RJ, Frackowiak RS, Robbins TW (1996b) Neural systems engaged by planning: a PET study of the Tower of London task. Neuropsychologia 34:515–526

    Article  PubMed  CAS  Google Scholar 

  • Bechara A (2003) Risky business: emotion, decision-making, and addiction. J Gambl Stud 19:23–51

    Article  PubMed  Google Scholar 

  • Bond AJ, Lader MH (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Cochran WG, Cox GM (1957) Experimental designs. Wiley, New York

    Google Scholar 

  • Collins P, Wilkinson LS, Everitt BJ, Robbins TW, Roberts AC (2000) The effect of dopamine depletion from the caudate nucleus of the common marmoset (Callithrix jacchus) on tests of prefrontal cognitive function. Behav Neurosci 114:3–17

    Article  PubMed  CAS  Google Scholar 

  • Cools R, Stefanova E, Barker RA, Robbins TW, Owen AM (2002) Dopaminergic modulation of high-level cognition in Parkinson’s disease: the role of prefrontal cortex revealed by PET. Brain 125:584–594

    Article  PubMed  Google Scholar 

  • D’Esposito M, Postle BR, Rypma B (2000) Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies. Exp Brain Res 133:3–11

    Article  PubMed  CAS  Google Scholar 

  • Diaz-Uriarte R (2002) Incorrect analysis of crossover trials in animal behaviour research. Anim Behav 63:815–822

    Article  Google Scholar 

  • Ellis KA, Mehta MA, Liley D, Wesnes K, Nathan PJ (2003) Effects of D1/D2 receptor stimulation on the short term spatial memory deficits induced by dopamine precursor depletion. J Psychopharmacol 17:A66

    Google Scholar 

  • Fern-Pollak L, Whone AL, Brooks DJ, Mehta MA (2004) Cognitive and motor effects of dopaminergic medication withdrawal in Parkinson’s disease. Neuropsychologia 42:1917–1926

    Article  PubMed  Google Scholar 

  • Gijsman HJ, Scarna A, Harmer CJ, McTavish SB, Odontiadis J, Cowen PJ, Goodwin GM (2002) A dose-finding study on the effects of branch chain amino acids on surrogate markers of brain dopamine function. Psychopharmacology (Berl) 160:192–197

    Article  CAS  Google Scholar 

  • Goel V, Grafman J (1995) Are the frontal lobes implicated in “planning” functions? Interpreting data from the Tower of Hanoi. Neuropsychologia 33:623–642

    Article  PubMed  CAS  Google Scholar 

  • Goldman-Rakic PS (1987) Circuitry of primate prefrontal cortex and regulation of behaviour by representational memory. In: Plum F (ed) Handbook of physiology; nervous system, Vol. 5. Higher functions of the brain (part 1). American Physiological Society, Bethesda, MD, pp 373–417

    Google Scholar 

  • Gotham AM, Brown RG, Marsden CD (1988) ‘Frontal’ cognitive function in patients with Parkinson’s disease ‘on’ and ‘off’ levodopa. Brain 111:299–321

    Article  PubMed  Google Scholar 

  • Harmer CJ, McTavish SF, Clark L, Goodwin GM, Cowen PJ (2001) Tyrosine depletion attenuates dopamine function in healthy volunteers. Psychopharmacology (Berl) 154:105–111

    Article  CAS  Google Scholar 

  • Harrison BJ, Olver JS, Norman TR, Burrows GD, Wesnes KA, Nathan PJ (2004) Selective effects of acute serotonin and catecholamine depletion on memory in healthy women. J Psychopharmacol 18:32–40

    Article  PubMed  CAS  Google Scholar 

  • Herbert M, Johns MW, Dore C (1976) Factor analysis of analogue scales measuring subjective feelings before and after sleep. Br J Med Psychol 49:373–379

    PubMed  CAS  Google Scholar 

  • Kimberg DY, D’Esposito M (2003) Cognitive effects of the dopamine receptor agonist pergolide. Neuropsychologia 41:1020–1027

    Article  PubMed  Google Scholar 

  • Kimberg DY, D’Esposito M, Farah MJ (1997) Effects of bromocriptine on human subjects depends on working memory capacity. NeuroReport 8:3581–3585

    Article  PubMed  CAS  Google Scholar 

  • Kimberg DY, Aguirre GK, Lease J, D’Esposito M (2001) Cortical effects of bromocriptine, a D-2 dopamine receptor agonist, in human subjects, revealed by fMRI. Hum Brain Mapp 12:246–257

    Article  PubMed  CAS  Google Scholar 

  • Lange KW, Robbins TW, Marsden CD, James M, Owen AM, Paul GM (1992) l-Dopa withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology 107:394–404

    Article  PubMed  CAS  Google Scholar 

  • Leyton M, Young SN, Pihl RO, Etezadi S, Lauze C, Blier P, Baker GB, Benkelfat C (1999) A comparison of the effects of acute trytophan depletion and acute phenylalanine/tyrosine depletion in healthy women. Adv Exp Med Biol 467:67–71

    PubMed  CAS  Google Scholar 

  • Luciana M, Collins PF (1997) Dopaminergic modulation of working memory for spatial but not object cues in normal volunteers. J Cogn Neurosci 9:330–347

    Google 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 4:58–67

    Google Scholar 

  • Luciana M, Collins PF, Depue RA (1998) Opposing roles for dopamine and serotonin in the modulation of human spatial working memory functions. Cereb Cortex 8:218–226

    Article  PubMed  CAS  Google Scholar 

  • Lueck CJ, Tanyeri S, Crawford TJ, Henderson L, Kennard C (1990) Antisaccades and remembered saccades in Parkinson’s disease. J Neurol Neurosurg Psychiatry 53:284–288

    PubMed  CAS  Google Scholar 

  • Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21:1034–1057

    Article  PubMed  CAS  Google Scholar 

  • McLean A, Rubinsztein JS, Robbins TW, Sahakian BJ (2004) The effects of tyrosine depletion in normal healthy volunteers: implications for unipolar depression. Psychopharmacology 171:286–297

    Article  PubMed  CAS  Google 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 13:379–384

    PubMed  CAS  Google Scholar 

  • McTavish SF, Cowen PJ, Sharp T (1999b) Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release. Psychopharmacology (Berl) 141:182–188

    Article  CAS  Google Scholar 

  • McTavish SF, McPherson MH, Sharp T, Cowen PJ (1999c) Attenuation of some subjective effects of amphetamine following tyrosine depletion. J Psychopharmacol 13:144–147

    PubMed  CAS  Google Scholar 

  • McTavish SF, Raumann B, Cowen PJ, Sharp T (2001) Tyrosine depletion attenuates the behavioural stimulant effects of amphetamine and cocaine in rats. Eur J Pharmacol 424:115–119

    Article  PubMed  CAS  Google Scholar 

  • 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 (Berl) 146:162–174

    Article  CAS  Google Scholar 

  • Mehta MA, Sahakian BJ, Robbins TW (2001a) Comparative psychopharmacology of methylphenidate and related drugs in human volunteers, patients with AD/HD and experimental animals. In: Solanto MV, Arnsten AFT, Castellanos FX (eds) Stimulant drugs and AD/HD: basic and clinical neuroscience. Oxford University Press, New York, pp 303–331

    Google Scholar 

  • Mehta MA, Swainson R, Ogilvie AD, Sahakian J, Robbins TW (2001b) Improved short-term spatial memory but impaired reversal learning following the dopamine D2 agonist bromocriptine in human volunteers. Psychopharmacology (Berl) 159:10–20

    Article  CAS  Google Scholar 

  • Mehta MA, McGowan S, Lawrence AD, Aitken MFR, Montgomery AJ, Grasby PM (2003) Systemic sulpiride modulates striatal blood flow: relationships to spatial working memory and planning. Neuroimage 20:1982–1994

    Article  PubMed  Google Scholar 

  • Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW (2004) Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D(2) receptor antagonist sulpiride in human volunteers. Psychopharmacology (Berl) (in press)

  • Mehta MA, Hinton EC, Montgomery AJ, Bantick RA, Grasby PM (2005) Sulpiride and mnemonic function: effects of a dopamine D2 receptor antagonist on working memory, emotional memory and long-term memory in healthy volunteers. J Psychopharmacol 19:31–40

    Article  Google Scholar 

  • Milner JD, Wurtman RJ (1986) Catecholamine synthesis: physiological coupling to precursor supply. Biochem Pharmacol 35:875–881

    Article  PubMed  CAS  Google Scholar 

  • Montgomery AJ, McTavish SFB, Cowen PJ, Grasby PM (2003) Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study. Am J Psychiatry 160:1887–1889

    Article  PubMed  Google Scholar 

  • Müller U, von Cramon DY, Pollmann S (1998) D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 18:2720–2728

    PubMed  Google Scholar 

  • Nelson HE, Willison JR (1991) The revised National Adult Reading Test—Test Manual. NFER-Nelson, UK

    Google Scholar 

  • Owen AM (1997) Cognitive planning in humans: neuropsychological, neuroanatomical and neuropharmacological perspectives. Prog Neurobiol 53:431–450

    Article  PubMed  CAS  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 28:1021–1034

    Article  PubMed  CAS  Google Scholar 

  • Owen AM, Sahakian BJ, Hodges JR, Polkey CE, Summers BA, Robbins TW (1995) Dopamine-dependent fronto-striatal planning deficits in early Parkinson’s disease. Neuropsychology 9:126–140

    Article  Google Scholar 

  • Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422:614–618

    Article  PubMed  CAS  Google Scholar 

  • Postle BR, Berger JS, D’Esposito M (1999) Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance. Proc Natl Acad Sci U S A 96:12959–12964

    Article  PubMed  CAS  Google Scholar 

  • Powell JH, al-Adawi S, Morgan J, Greenwood RJ (1996) Motivational deficits after brain injury: effects of bromocriptine in 11 patients. J Neurol Neurosurg Psychiatry 60:416–421

    Article  PubMed  CAS  Google Scholar 

  • Rahman S, B JS, R NC, Rogers R, Robbins T (2001) Decision making and neuropsychiatry. Trends Cogn Sci 5:271–277

    Article  PubMed  Google Scholar 

  • Roberts AC, De Salvia MA, Wilkinson LS, Collins P, Muir JL, Everitt BJ, Robbins TW (1994) 6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine. J Neurosci 14:2531–2544

    PubMed  CAS  Google Scholar 

  • Roiser J, McLean A, Ogilvie AD, Blackwell A, Sahakian BJ (2004) The effects of acute tyrosine and phenylalanine depletion in recovered depression. J Psychopharmacol 18:A16

    Article  Google Scholar 

  • Rowe JB, Passingham RE (2001) Working memory for location and time: activity in prefrontal area 46 relates to selection rather than maintenance in memory. Neuroimage 14:77–86

    Article  PubMed  CAS  Google Scholar 

  • Rowe JB, Owen AM, Johnsrude IS, Passingham RE (2001) Imaging the mental components of a planning task. Neuropsychologia 39:315–327

    Article  PubMed  CAS  Google Scholar 

  • Schultz W (1998) The phasic reward signal of primate dopamine neurons. Adv Pharmacol 42:686–690

    Article  PubMed  CAS  Google Scholar 

  • Spinks TJ, Jones T, Bloomfield PM, Bailey DL, Miller M, Hogg D, Jones WF, Vaigneur K, Reed J, Young J, Newport D, Moyers C, Casey ME, Nutt R (2000) Physical characteristics of the ECAT EXACT3D positron tomograph. Phys Med Biol 45:2601–2618

    Article  PubMed  CAS  Google Scholar 

  • Swainson R, Rogers RD, Sahakian BJ, Summers BA, Polkey CE, Robbins TW (2000) Probabilistic learning and reversal deficits in patients with Parkinson’s disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication. Neuropsychologia 38:596–612

    Article  PubMed  CAS  Google Scholar 

  • Tam SY, Roth RH (1997) Mesoprefrontal dopaminergic neurons: can tyrosine availability influence their functions? Biochem Pharmacol 53:441–453

    Article  PubMed  CAS  Google Scholar 

  • Tam SY, D. EJ, W. BC, Roth RH (1990) Mesocortical dopamine neurons: high basal firing frequency predicts tyrosine dependence of dopamine synthesis. J Neural Transm 81:97–110

    Article  CAS  Google Scholar 

  • Tannock R, Schachar RJ, Carr RP, Chajczyk D, Logan GD (1989) Effects of methylphenidate on inhibitory control in hyperactive children. J Abnorm Child Psychol 17:473–491

    Article  PubMed  CAS  Google Scholar 

  • Watabe H, Endres CJ, Breier A, Schmall B, Eckelman WC, Carson RE (2000) Measurement of dopamine release with continuous infusion of [11C]raclopride: optimization and signal-to-noise considerations. J Nucl Med 41:522–530

    PubMed  CAS  Google Scholar 

  • Weschler D (1981) Weschler adult intelligence scale—revised. Psychological Corporation, San Antonio, TX

    Google Scholar 

  • Young AM, Ahier RG, Upton RL, Joseph MH, Gray JA (1998) Increased extracellular dopamine in the nucleus accumbens of the rat during associative learning of neutral stimuli. Neuroscience 83:1175–1183

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank those that volunteered for and participated in this study, which was supported by the Medical Research Council, UK. M.A.M. was supported by an MRC (non-clinical) Research Training Fellowship. A.J.M. was supported by a Wellcome Trust Clinical Research Training Fellowship.

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Correspondence to Mitul A. Mehta.

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Mehta, M.A., Gumaste, D., Montgomery, A.J. et al. The effects of acute tyrosine and phenylalanine depletion on spatial working memory and planning in healthy volunteers are predicted by changes in striatal dopamine levels. Psychopharmacology 180, 654–663 (2005). https://doi.org/10.1007/s00213-004-2128-8

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  • DOI: https://doi.org/10.1007/s00213-004-2128-8

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