Advertisement

Psychopharmacology

, Volume 196, Issue 2, pp 221–232 | Cite as

Single dose of a dopamine agonist impairs reinforcement learning in humans: Behavioral evidence from a laboratory-based measure of reward responsiveness

  • Diego A. Pizzagalli
  • A. Eden Evins
  • Erika Cowman Schetter
  • Michael J. Frank
  • Petra E. Pajtas
  • Diane L. Santesso
  • Melissa Culhane
Original Investigation

Abstract

Rationale

The dopaminergic system, particularly D2-like dopamine receptors, has been strongly implicated in reward processing. Animal studies have emphasized the role of phasic dopamine (DA) signaling in reward-related learning, but these processes remain largely unexplored in humans.

Objectives

To evaluate the effect of a single, low dose of a D2/D3 agonist—pramipexole—on reinforcement learning in healthy adults. Based on prior evidence indicating that low doses of DA agonists decrease phasic DA release through autoreceptor stimulation, we hypothesized that 0.5 mg of pramipexole would impair reward learning due to presynaptic mechanisms.

Materials and methods

Using a double-blind design, a single 0.5-mg dose of pramipexole or placebo was administered to 32 healthy volunteers, who performed a probabilistic reward task involving a differential reinforcement schedule as well as various control tasks.

Results

As hypothesized, response bias toward the more frequently rewarded stimulus was impaired in the pramipexole group, even after adjusting for transient adverse effects. In addition, the pramipexole group showed reaction time and motor speed slowing and increased negative affect; however, when adverse physical side effects were considered, group differences in motor speed and negative affect disappeared.

Conclusions

These findings show that a single low dose of pramipexole impaired the acquisition of reward-related behavior in healthy participants, and they are consistent with prior evidence suggesting that phasic DA signaling is required to reinforce actions leading to reward. The potential implications of the present findings to psychiatric conditions, including depression and impulse control disorders related to addiction, are discussed.

Keywords

Dopamine D2 agonists Reward processing Depression Mesolimbic system Addiction 

Notes

Acknowledgments

This work was supported by grants from NIMH (R01 MH68376; DAP) and Harvard College Research Program (ECS). Dr. Evins and Ms. Culhane were supported by a grant from the National Institute on Drug Abuse (K23 DA00510-01; AEE). Dr. Frank was supported by a grant from the National Institute on Drug Abuse (DA022630). The authors would like to thank Dr. Catherine Fullerton, Kyle Ratner, Elena Goetz, and Jeffrey Birk for their assistance with the project, Dr. David Standaert for his helpful review of the results, and three anonymous reviewers for their constructive criticisms.

Disclosure/Conflict of interest statement

Dr. Pizzagalli has received research support from GlaxoSmithKline and Merck & Co., manufacturers of antidepressants. Dr. Evins has received research grant support from Janssen Pharmaceutica, Sanofi-Aventis, Astra Zeneca; research materials from GSK and Pfizer, and honoraria from Primedia. Moreover, Dr. Evins is an investigator in a NIDA-funded collaborative study with GSK. Dr. Frank, Ms. Schetter, Ms. Culhane, and Ms. Pajtas report no competing interests.

References

  1. Baudry M, Martres MP, Schwartz JC (1977) In vivo binding of 3H-pimozide in mouse striatum: effects of dopamine agonists and antagonists. Life Sci 21:1163–1170PubMedCrossRefGoogle Scholar
  2. Bayer HM, Glimcher PW (2005) Midbrain dopamine neurons encode a quantitative reward prediction error signal. Neuron 47:129–141PubMedCrossRefGoogle Scholar
  3. Beck AT, Steer RA, Brown GK (1996) Beck depression inventory manual, 2nd edn. The Psychological Corporation, San Antonio, TXGoogle Scholar
  4. Bogdan R, Pizzagalli DA (2006) Acute stress reduces reward responsiveness: implications for depression. Biol Psychiatry 60:1147–1154PubMedCrossRefGoogle Scholar
  5. Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218Google Scholar
  6. Cassano P, Lattanzi L, Soldani F, Navari S, Mattistini G, Gemignani A, Cassano G (2004) Pramipexole in treatment-resistant depression: an extended follow-up. Depress Anxiety 20:131–138PubMedCrossRefGoogle Scholar
  7. Chapman LJ, Chapman JP (1987) The measurement of handedness. Brain Cogn 6:175–183PubMedCrossRefGoogle Scholar
  8. Chen YC, Choi JK, Andersen SL, Rosen BR, Jenkins BG (2005) Mapping dopamine D2/D3 receptor function using pharmacological magnetic resonance imaging. Psychopharmacology (Berl) 180:705–715CrossRefGoogle Scholar
  9. Cheng J, Feenstra MG (2006) Individual differences in dopamine efflux in nucleus accumbens shell and core during instrumental learning. Learn Mem 13:168–177PubMedCrossRefGoogle Scholar
  10. Civelli O (2000) Molecular biology of dopamine receptor subtypes. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven, New YorkGoogle Scholar
  11. Cools R, Altamirano L, D’Esposito M (2006) Reversal learning in Parkinson’s disease depends on medication status and outcome valence. Neuropsychologia 44:1663–1673PubMedCrossRefGoogle Scholar
  12. Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW (2007) L-DOPA disrupts activity in the nucleus accumbens during reversal learning in Parkinson’s disease. Neuropsychopharmacology 32:180–189PubMedCrossRefGoogle Scholar
  13. Cooper JR, Bloom FE, Roth RH (2003) The biochemical basis of neuropharmacology, 8th edn. Oxford University Press, OxfordGoogle Scholar
  14. Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL (2000) Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11:58–65PubMedCrossRefGoogle Scholar
  15. de Wit H, Enggasser JL, Richards JB (2002) Acute administration of d-amphetamine decreases impulsivity in healthy volunteers. Neuropsychopharmacology 27:813–825PubMedCrossRefGoogle Scholar
  16. Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337PubMedCrossRefGoogle Scholar
  17. Ferreira JJ, Galitzky M, Thalamas C, Tiberge M, Montastruc JL, Sampaio C, Rascol O (2002) Effect of ropinirole on sleep onset: a randomized, placebo-controlled study in healthy volunteers. Neurology 58:460–462PubMedGoogle Scholar
  18. Fiorillo CD, Tobler PN, Schultz W (2003) Discrete coding of reward probability and uncertainty by dopamine neurons. Science 299:1898–1902PubMedCrossRefGoogle Scholar
  19. First MB, Spitzer RL, Gibbon M, Williams JBW (2002) Structured clinical interview for DSM-IV-TR axis I disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, New YorkGoogle Scholar
  20. Frank MJ (2005) Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism. J Cogn Neurosci 17:51–72PubMedCrossRefGoogle Scholar
  21. Frank MJ, O’Reilly RC (2006) A mechanistic account of striatal dopamine function in human cognition: psychopharmacological studies with cabergoline and haloperidol. Behav Neurosci 120:497–517PubMedCrossRefGoogle Scholar
  22. Frank MJ, Seeberger LC, O’Reilly RC (2004) By carrot or by stick: cognitive reinforcement learning in parkinsonism. Science 306:1940–1943PubMedCrossRefGoogle Scholar
  23. Fuller RW, Clemens JA, Hynes MD 3rd (1982) Degree of selectivity of pergolide as an agonist at presynaptic versus postsynaptic dopamine receptors: implications for prevention or treatment of tardive dyskinesia. J Clin Psychopharmacol 2:371–375PubMedCrossRefGoogle Scholar
  24. Garris PA, Kilpatrick M, Bunin MA, Michael D, Walker QD, Wightman RM (1999) Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation. Nature 398:67–69PubMedCrossRefGoogle Scholar
  25. Giovannoni G, van Schalkwyk J, Fritz VU, Lees AJ (1999) Bradykinesia akinesia inco-ordination test (BRAIN TEST): an objective computerised assessment of upper limb motor function. J Neurol Neurosurg Psychiatry 67:624–629PubMedCrossRefGoogle Scholar
  26. Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1–24PubMedCrossRefGoogle Scholar
  27. Grace AA (2002) Dopamine. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds) Neuropsychopharmacology: the fifth generation of progress. Lippincott Williams & Wilkins, Philadelphia, pp 119–132Google Scholar
  28. Harrison BJ, Olver JS, Norman TR, Nathan PJ (2002) Effects of serotonin and catecholamine depletion on interleukin-6 activation and mood in human volunteers. Hum Psychopharmacol 17:293–297PubMedCrossRefGoogle Scholar
  29. Hollerman JR, Schultz W (1998) Dopamine neurons report an error in the temporal prediction of reward during learning. Nat Neurosci 1:304–309PubMedCrossRefGoogle Scholar
  30. Holroyd CB, Coles MGH (2002) The neural basis of human error processing: reinforcement learning, dopamine, and the error-related negativity. Psychol Rev 109:679–709PubMedCrossRefGoogle Scholar
  31. Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson’s disease. Adv Neurol 45:19–34PubMedGoogle Scholar
  32. Ikemoto S, Panksepp J (1996) Dissociations between appetitive and consummatory responses by pharmacological manipulations of reward-relevant brain regions. Behav Neurosci 110:331–345PubMedCrossRefGoogle Scholar
  33. Keating GL, Rye DB (2003) Where you least expect it: dopamine in the pons and modulation of sleep and REM-sleep. Sleep 26:788–789PubMedGoogle Scholar
  34. Lefoll B, Diaz J, Sokoloff P (2005) Neuroadaptations to hyperdopaminergia in dopamine D3-receptor deficient mice. Life Sci 76:1281–1296CrossRefGoogle Scholar
  35. Lehr E (2002) Potential antidepressant properties of pramipexole detected in locomotor and operant behavioral investigations in mice. Psychopharmacology 163:495–500PubMedCrossRefGoogle Scholar
  36. Lemke MR, Brecht HM, Koester J, Reichmann H (2006) Effects of the dopamine agonist pramipexole on depression, anhedonia and motor functioning in Parkinson’s disease. J Neurol Sci 248:266–270PubMedCrossRefGoogle Scholar
  37. Leyton M, aan het Rot M, Booij L, Baker GB, Young SN, Benkelfat C (2007) Moodelevating effects of d-amphetamine and incentive salience: the effect of acute dopamine precursor depletion. J Psychiatry Neurosci 32:129–136PubMedGoogle Scholar
  38. Maj J, Rogoz Z (1999) Synsergic effect of pramipexole and sertraline in the forced swimming test. Pol J Pharmacol 51:471–475PubMedGoogle Scholar
  39. Montague PR, Dayan P, Sejnowski TJ (1996) A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J Neurosci 16:1936–1947PubMedGoogle Scholar
  40. Montague PR, Hyman SE, Cohen JD (2004) Computational roles for dopamine in behavioural control. Nature 431:760–767PubMedCrossRefGoogle Scholar
  41. Monti JM, Hawkins M, Jantos H, D’Angelo L, Fernandez M (1988) Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat. Psychopharmacology 95:395–400PubMedCrossRefGoogle Scholar
  42. Myers RE, Anderson LI, Dluzen DE (2003) Estrogen, but not testosterone, attenuates methamphetamine-evoked dopamine output from superfused striatal tissue of female and male mice. Neuropharmacology 44:624–632PubMedCrossRefGoogle Scholar
  43. Nagy H, Keri S, Myers CE, Benedek G, Shohamy D, Gluck MA (2007) Cognitive sequence learning in Parkinson’s disease and amnestic mild cognitive impairment: dissociation between sequential and non-sequential learning of associations. Neuropsychologia 45:1386–1392PubMedCrossRefGoogle Scholar
  44. Parkinson Study Group (2000) Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Parkinson Study Group. JAMA 284:1931–1938CrossRefGoogle Scholar
  45. Parkinson JA, Dalley JW, Cardinal RN, Bamford A, Fehnert B, Lachenal G, Rudarakanchana N, Halkerston KM, Robbins TW, Everitt BJ (2002) Nucleus accumbens dopamine depletion impairs both acquisition and performance of appetitive Pavlovian approach behaviour: implications for mesoaccumbens dopamine function. Behav Brain Res 137:149–163PubMedCrossRefGoogle Scholar
  46. Perbal S, Couillet J, Azouvi P, Pouthas V (2003) Relationships between time estimation, memory, attention, and processing speed in patients with severe traumatic brain injury. Neuropsychologia 41:1599–1610PubMedCrossRefGoogle Scholar
  47. Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD (2006) Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 442:1042–1045PubMedCrossRefGoogle Scholar
  48. Piercey MF, Hoffmann WE, Smith MW, Hyslop DK (1996) Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other dopamine receptor agonists. Eur J Pharmacol 312:35–44PubMedCrossRefGoogle Scholar
  49. Pizzagalli DA, Jahn AL, O’Shea JP (2005) Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. Biol Psychiatry 57:319–327PubMedCrossRefGoogle Scholar
  50. Reynolds JN, Hyland BI, Wickens JR (2001) A cellular mechanism of reward-related learning. Nature 413:67–70PubMedCrossRefGoogle Scholar
  51. Robinson S, Rainwater AJ, Hnasko TS, Palmiter RD (2007) Viral restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice. Psychopharmacology (Berl) 191:567–578CrossRefGoogle Scholar
  52. Rye DB (2004) The two faces of Eve: dopamine’s modulation of wakefulness and sleep. Neurology 63(8 Suppl 3):S2–S7PubMedGoogle Scholar
  53. Rye DB, Jankovic J (2002) Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology 58:341–346Google Scholar
  54. Samuels ER, Hou RH, Langley RW, Szabadi E, Bradshaw CM (2006a) Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers. Psychopharmacology (Berl) 187:498–510CrossRefGoogle Scholar
  55. Samuels ER, Hou RH, Langley RW, Szabadi E, Bradshaw CM (2006b) Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers. J Psychopharmacol 20:756–770PubMedCrossRefGoogle Scholar
  56. Schmitz Y, Benoit-Marand M, Gonon F, Sulzer D (2003) Presynaptic regulation of dopaminergic neurotransmission. J Neurochem 87:273–289PubMedCrossRefGoogle Scholar
  57. Schuck S, Bentue-Ferrer D, Kleinermans D, Reymann JM, Polard E, Gandon JM, Allain H (2002) Psychomotor and cognitive effects of piribedil, a dopamine agonist, in young healthy volunteers. Fundam Clin Pharmacol 16:57–65PubMedCrossRefGoogle Scholar
  58. Schultz W (2002) Getting formal with dopamine and reward. Neuron 36:241–263PubMedCrossRefGoogle Scholar
  59. Schultz W (2007) Behavioral dopamine signals. Trends Neurosci 30:203–210PubMedCrossRefGoogle Scholar
  60. Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593–1599PubMedCrossRefGoogle Scholar
  61. Schwabe K, Koch M (2007) Effects of aripiprazole on operant responding for a natural reward after psychostimulant withdrawal in rats. Psychopharmacology (Berl) 191:759–765CrossRefGoogle Scholar
  62. Servan-Schreiber D, Carter CS, Bruno RM, Cohen JD (1998) Dopamine and the mechanisms of cognition: Part II. D-amphetamine effects in human subjects performing a selective attention task. Biol Psychiatry 43:723–729PubMedCrossRefGoogle Scholar
  63. Sevy S, Hassoun Y, Bechara A, Yechiam E, Napolitano B, Burdick K, Delman H, Malhotra A (2006) Emotion-based decision-making in healthy subjects: short-term effects of reducing dopamine levels. Psychopharmacology (Berl) 188:228–235CrossRefGoogle Scholar
  64. Shohamy D, Myers CE, Grossman S, Sage J, Gluck MA (2005) The role of dopamine in cognitive sequence learning: evidence from Parkinson’s disease. Behav Brain Res 156:191–199PubMedCrossRefGoogle Scholar
  65. Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, Gross C (2006) The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 5:25–43PubMedGoogle Scholar
  66. Sokolowski JD, Conlan AN, Salamone JD (1998) A microdialysis study of nucleus accumbens core and shell dopamine during operant responding in the rat. Neuroscience 86:1001–1009PubMedCrossRefGoogle Scholar
  67. Spielberger CD, Gorsuch RL, Lushere RE (1970) Manual of the state-trait anxiety inventory. Consulting Psychologists, Palo Alto, CAGoogle Scholar
  68. Sumners C, de Vries JB, Horn AS (1981) Behavioural and neurochemical studies on apomorphine-induced hypomotility in mice. Neuropharmacology 20:1203–1208PubMedCrossRefGoogle Scholar
  69. Tissari AH, Rossetti ZL, Meloni M, Frau MI, Gessa GL (1983) Autoreceptors mediate the inhibition of dopamine synthesis by bromocriptine and lisuride in rats. Eur J Pharmacol 91:463–468PubMedCrossRefGoogle Scholar
  70. Tripp G, Alsop B (1999) Sensitivity to reward frequency in boys with attention deficit hyperactivity disorder. J Clin Child Psychol 28:366–375PubMedCrossRefGoogle Scholar
  71. Waelti P, Dickinson A, Schultz W (2001) Dopamine responses comply with basic assumptions of formal learning theory. Nature 412:43–48PubMedCrossRefGoogle Scholar
  72. Weintraub D, Siderowf AD, Potenza MN, Goveas J, Morales KH, Duda JE, Moberg PJ, Stern MB (2006) Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 63:969–973PubMedCrossRefGoogle Scholar
  73. Willner P (1995) Dopaminergic mechanisms in depression and mania. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven, New York, pp 921–931Google Scholar
  74. Willner P, Lappas S, Cheeta S, Muscat R (1994) Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole. Psychopharmacology 115:454–462PubMedCrossRefGoogle Scholar
  75. Wright CE, Sisson TL, Ichhpurani AK, Peters GR (1997) Steady-state pharmacokinetic properties of pramipexole in healthy volunteers. J Clin Pharmacol 37:520–525PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Diego A. Pizzagalli
    • 1
  • A. Eden Evins
    • 2
  • Erika Cowman Schetter
    • 1
  • Michael J. Frank
    • 3
  • Petra E. Pajtas
    • 1
  • Diane L. Santesso
    • 1
  • Melissa Culhane
    • 2
  1. 1.Department of PsychologyHarvard UniversityCambridgeUSA
  2. 2.Department of PsychiatryMassachusetts General HospitalBostonUSA
  3. 3.Department of PsychologyUniversity of ArizonaTucsonUSA

Personalised recommendations