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Vol. 11, No. 2, 2013
Issue release date: November 2012
Neurodegener Dis 2013;11:102–111
(DOI:10.1159/000341999)

Dissociating the Cognitive Effects of Levodopa versus Dopamine Agonists in a Neurocomputational Model of Learning in Parkinson’s Disease

Moustafa A.A. · Herzallah M.M. · Gluck M.A.
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Abstract

Background/Aims: Levodopa and dopamine agonists have different effects on the motor, cognitive, and psychiatric aspects of Parkinson’s disease (PD). Methods: Using a computational model of basal ganglia (BG) and prefrontal cortex (PFC) dopamine, we provide a theoretical synthesis of the dissociable effects of these dopaminergic medications on brain and cognition. Our model incorporates the findings that levodopa is converted by dopamine cells into dopamine, and thus activates prefrontal and striatal D1 and D2 dopamine receptors, whereas antiparkinsonian dopamine agonists directly stimulate D2 receptors in the BG and PFC (although some have weak affinity to D1 receptors). Results: In agreement with prior neuropsychological studies, our model explains how levodopa enhances, but dopamine agonists impair or have no effect on, stimulus-response learning and working memory. Conclusion: Our model explains how levodopa and dopamine agonists have differential effects on motor and cognitive processes in PD.



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References

  1. Trugman JM, James CL, Wooten GF: D1/D2 dopamine receptor stimulation byL-dopa. A [14C]-2-deoxyglucose autoradiographic study. Brain 1991;114:1429–1440.

    External Resources

  2. Muriel MP, Orieux G, Hirsch EC: Levodopa but not ropinirole induces an internalization of D1 dopamine receptors in parkinsonian rats. Mov Disord 2002;17:1174–1179.

    External Resources

  3. Grace AA: Physiology of the normal and dopamine-depleted basal ganglia: insights into levodopa pharmacotherapy. Mov Disord 2008;23(suppl 3):S560–S569.

    External Resources

  4. Sammut S, Dec A, Mitchell D, Linardakis J, Ortiguela M, West AR: Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D(1/5) receptor-dependent mechanism. Neuropsychopharmacology 2006;31:493–505.
  5. Ballion B, Frenois F, Zold CL, Chetrit J, Murer MG, Gonon F: D2 receptor stimulation, but not D1, restores striatal equilibrium in a rat model of parkinsonism. Neurobiol Dis 2009;35:376–384.
  6. Dreyer JK, Herrik KF, Berg RW, Hounsgaard JD: Influence of phasic and tonic dopamine release on receptor activation. J Neurosci 2010;30:14273–14283.
  7. Hauber W: Dopamine release in the prefrontal cortex and striatum: temporal and behavioural aspects. Pharmacopsychiatry 2010;43(suppl 1):S32–S41.

    External Resources

  8. Harden DG, Grace AA: Activation of dopamine cell firing by repeated L-DOPA administration to dopamine-depleted rats: its potential role in mediating the therapeutic response to L-DOPA treatment. J Neurosci 1995;15:6157–6166.
  9. Reynolds JN, Hyland BI, Wickens JR: A cellular mechanism of reward-related learning. Nature 2001;413:67–70.
  10. Tsai HC, Zhang F, Adamantidis A, Stuber GD, Bonci A, de Lecea L, Deisseroth K: Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 2009;324:1080–1084.
  11. Gerfen CR: The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia. Annu Rev Neurosci 1992;15:285–320.
  12. Goldman-Rakic PS: Cellular basis of working memory. Neuron 1995;14:477–485.
  13. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M: Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;22:3708–3719.
  14. Seamans JK, Yang CR: The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 2004;74:1–58.
  15. Williams GV, Goldman-Rakic PS: Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995;376:572–575.
  16. Cohen JD, Braver TS, Brown JW: Computational perspectives on dopamine function in prefrontal cortex. Curr Opin Neurobiol 2002;12:223–229.
  17. McNab F, Varrone A, Farde L, Jucaite A, Bystritsky P, Forssberg H, Klingberg T: Changes in cortical dopamine D1 receptor binding associated with cognitive training. Science 2009;323:800–802.
  18. Wang M, Vijayraghavan S, Goldman-Rakic PS: Selective D2 receptor actions on the functional circuitry of working memory. Science 2004;303:853–856.
  19. Huang YY, Simpson E, Kellendonk C, Kandel ER: Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc Natl Acad Sci USA 2004;101:3236–3241.
  20. Knecht S, Breitenstein C, Bushuven S, Wailke S, Kamping S, Floel A, Zwitserlood P, Ringelstein EB: Levodopa: faster and better word learning in normal humans. Ann Neurol 2004;56:20–26.
  21. Pavlis M, Feretti C, Levy A, Gupta N, Linster C: L-DOPA improves odor discrimination learning in rats. Physiol Behav 2006;87:109–113.
  22. Gotham AM, Brown RG, Marsden CD: ‘Frontal’ cognitive function in patients with Parkinson’s disease ‘on’ and ‘off’ levodopa. Brain 1988;111:299–321.

    External Resources

  23. Scheidtmann K, Fries W, Muller F, Koenig E: Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet 2001;358:787–790.
  24. Rosser N, Heuschmann P, Wersching H, Breitenstein C, Knecht S, Floel A: Levodopa improves procedural motor learning in chronic stroke patients. Arch Phys Med Rehabil 2008;89:1633–1641.
  25. Pleger B, Ruff CC, Blankenburg F, Kloppel S, Driver J, Dolan RJ: Influence of dopaminergically mediated reward on somatosensory decision-making. PLoS Biol 2009;7:e1000164.

    External Resources

  26. Robinson S, Rainwater AJ, Hnasko TS, Palmiter RD: Viral restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice. Psychopharmacology (Berl) 2007;191:567–578.
  27. Graef S, Biele G, Krugel LK, Marzinzik F, Wahl M, Wotka J, Klostermann F, Heekeren HR: Differential influence of levodopa on reward-based learning in Parkinson’s disease. Front Hum Neurosci 2010;4:169.

    External Resources

  28. Floel A, Vomhof P, Lorenzen A, Roesser N, Breitenstein C, Knecht S: Levodopa improves skilled hand functions in the elderly. Eur J Neurosci 2008;27:1301–1307.

    External Resources

  29. Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD: Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 2006;442:1042–1045.
  30. Beeler JA, Cao ZF, Kheirbek MA, Ding Y, Koranda J, Murakami M, Kang UJ, Zhuang X: Dopamine-dependent motor learning: insight into levodopa’s long-duration response. Ann Neurol 2010;67:639–647.
  31. de Vries MH, Ulte C, Zwitserlood P, Szymanski B, Knecht S: Increasing dopamine levels in the brain improves feedback-based procedural learning in healthy participants: an artificial-grammar-learning experiment. Neuropsychologia 2010;48:3193–3197.

    External Resources

  32. Breitenstein C, Korsukewitz C, Floel A, Kretzschmar T, Diederich K, Knecht S: Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Neuropsychopharmacology 2006;31:2552–2564.
  33. Pizzagalli DA, Evins AE, Schetter EC, Frank MJ, Pajtas PE, Santesso DL, Culhane M: Single dose of a dopamine agonist impairs reinforcement learning in humans: behavioral evidence from a laboratory-based measure of reward responsiveness. Psychopharmacology (Berl) 2008;196:221–232.
  34. Frank MJ, O’Reilly RC: A mechanistic account of striatal dopamine function in human cognition: psychopharmacological studies with cabergoline and haloperidol. Behav Neurosci 2006;120:497–517.
  35. Santesso DL, Evins AE, Frank MJ, Schetter EC, Bogdan R, Pizzagalli DA: Single dose of a dopamine agonist impairs reinforcement learning in humans: evidence from event-related potentials and computational modeling of striatal-cortical function. Hum Brain Mapp 2009;30:1963–1976.

    External Resources

  36. McClure MM, Harvey PD, Goodman M, Triebwasser J, New A, Koenigsberg HW, Sprung LJ, Flory JD, Siever LJ: Pergolide treatment of cognitive deficits associated with schizotypal personality disorder: continued evidence of the importance of the dopamine system in the schizophrenia spectrum. Neuropsychopharmacology 2010;35:1356–1362.
  37. Feigin A, Ghilardi MF, Carbon M, Edwards C, Fukuda M, Dhawan V, Margouleff C, Ghez C, Eidelberg D: Effects of levodopa on motor sequence learning in Parkinson’s disease. Neurology 2003;60:1744–1749.
  38. Shohamy D, Myers CE, Geghman KD, Sage J, Gluck MA: L-DOPA impairs learning, but spares generalization, in Parkinson’s disease. Neuropsychologia 2006;44:774–784.

    External Resources

  39. Jahanshahi M, Wilkinson L, Gahir H, Dharminda A, Lagnado DA: Medication impairs probabilistic classification learning in Parkinson’s disease. Neuropsychologia 2010;48:1096–1103.

    External Resources

  40. Housden CR, O’Sullivan SS, Joyce EM, Lees AJ, Roiser JP: Intact reward learning but elevated delay discounting in Parkinson’s disease patients with impulsive-compulsive spectrum behaviors. Neuropsychopharmacology 2010;35:2155–2164.
  41. Mongeon D, Blanchet P, Messier J: Impact of Parkinson’s disease and dopaminergic medication on proprioceptive processing. Neuroscience 2009;158:426–440.
  42. Lange KW, Robbins TW, Marsden CD, James M, Owen AM, Paul GM: L-DOPA withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology (Berl) 1992;107:394–404.
  43. Lewis SJ, Slabosz A, Robbins TW, Barker RA, Owen AM: Dopaminergic basis for deficits in working memory but not attentional set-shifting in Parkinson’s disease. Neuropsychologia 2005;43:823–832.

    External Resources

  44. Beato R, Levy R, Pillon B, Vidal C, du Montcel ST, Deweer B, Bonnet AM, Houeto JL, Dubois B, Cardoso F: Working memory in Parkinson’s disease patients: clinical features and response to levodopa. Arq Neuropsiquiatr 2008;66:147–151.

    External Resources

  45. Marini P, Ramat S, Ginestroni A, Paganini M: Deficit of short-term memory in newly diagnosed untreated parkinsonian patients: reversal after L-DOPA therapy. Neurol Sci 2003;24:184–185.
  46. Brusa L, Bassi A, Stefani A, Pierantozzi M, Peppe A, Caramia MD, Boffa L, Ruggieri S, Stanzione P: Pramipexole in comparison to L-DOPA: a neuropsychological study. J Neural Transm 2003;110:373–380.
  47. Costa A, Peppe A, Dell’Agnello G, Carlesimo GA, Murri L, Bonuccelli U, Caltagirone C: Dopaminergic modulation of visual-spatial working memory in Parkinson’s disease. Dement Geriatr Cogn Disord 2003;15:55–66.
  48. Pascual-Sedano B, Kulisevsky J, Barbanoj M, Garcia-Sanchez C, Campolongo A, Gironell A, Pagonabarraga J, Gich I: Levodopa and executive performance in Parkinson’s disease: a randomized study. J Int Neuropsychol Soc 2008;14:832–841.
  49. Fernandez-Ruiz J, Doudet D, Aigner TG: Spatial memory improvement by levodopa in parkinsonian MPTP-treated monkeys. Psychopharmacology (Berl) 1999;147:104–107.
  50. Brusa L, Tiraboschi P, Koch G, Peppe A, Pierantozzi M, Ruggieri S, Stanzione P: Pergolide effect on cognitive functions in early-mild Parkinson’s disease. J Neural Transm 2005;112:231–237.
  51. McDowell S, Whyte J, D’Esposito M: Differential effect of a dopaminergic agonist on prefrontal function in traumatic brain injury patients. Brain 1998;121:1155–1164.

    External Resources

  52. Moustafa, Gluck MA: A neurocomputational model of dopamine and prefrontal-striatal interactions during multicue category learning by Parkinson patients. J Cogn Neurosci 2011;23:151–167.

    External Resources

  53. Guthrie M, Myers CE, Gluck MA: A neurocomputational model of tonic and phasic dopamine in action selection: a comparison with cognitive deficits in Parkinson’s disease. Behav Brain Res 2009;200:48–59.
  54. Suri RE, Schultz W: Learning of sequential movements by neural network model with dopamine-like reinforcement signal. Exp Brain Res 1998;121:350–354.
  55. Suri RE, Schultz W: A neural network model with dopamine-like reinforcement signal that learns a spatial delayed response task. Neuroscience 1999;91:871–890.
  56. Houk JC: Information processing in modular circuits linking basal ganglia and cerebral cortex; in Houk JC, Davis JL, Beiser DG (eds): Models of Information Processing in the Basal Ganglia. Cambridge, MIT Press, 1995, pp xii, 382.
  57. Frank MJ: Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated parkinsonism. J Cogn Neurosci 2005;17:51–72.
  58. Ashby FG, Ell SW, Valentin VV, Casale MB: Frost: a distributed neurocomputational model of working memory maintenance. J Cogn Neurosci 2005;17:1728–1743.

    External Resources

  59. Muller U, von Cramon DY, Pollmann S: D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 1998;18:2720–2728.
  60. Moustafa AA, Maida AS: Using TD learning to simulate working memory performance in a model of the prefrontal cortex and basal ganglia. Cogn Syst Res 2007;8:262–281.

    External Resources

  61. Gibbs SE, D’Esposito M: A functional MRI study of the effects of bromocriptine, a dopamine receptor agonist, on component processes of working memory. Psychopharmacology (Berl) 2005;180:644–653.
  62. Luciana M, Depue RA, Arbisi P, Leon A: Facilitation of working memory in humans by a D2 dopamine receptor agonist. J Cogn Neurosci 1992;4:58–68.

    External Resources

  63. Sultzer DL, Levin HS, Mahler ME, High WM, Cummings JL: Assessment of cognitive, psychiatric, and behavioral disturbances in patients with dementia: the neurobehavioral rating scale. J Am Geriatr Soc 1992;40:549–555.
  64. Taverna S, Ilijic E, Surmeier DJ: Recurrent collateral connections of striatal medium spiny neurons are disrupted in models of Parkinson’s disease. J Neurosci 2008;28:5504–5512.
  65. Trantham-Davidson H, Neely LC, Lavin A, Seamans JK: Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 2004;24:10652–10659.
  66. Grace AA: Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 1991;41:1–24.
  67. Moustafa AA, Cohen MX, Sherman SJ, Frank MJ: A role for dopamine in temporal decision making and reward maximization in parkinsonism. J Neurosci 2008;28:12294–12304.
  68. Durstewitz D, Seamans JK, Sejnowski TJ: Neurocomputational models of working memory. Nat Neurosci 2000;3(suppl):1184– 1191.

    External Resources

  69. Arnsten AF, Cai JX, Steere JC, Goldman-Rakic PS: Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys. J Neurosci 1995;15:3429–3439.
  70. Helie S, Paul EJ, Ashby FG: A neurocomputational account of cognitive deficits in Parkinson’s disease. Neuropsychologia 2012;50:2290–2302.

    External Resources

  71. Laszy J, Laszlovszky I, Gyertyan I: Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl) 2005;179:567–575.
  72. Phillips GD, Morutto SL: Post-session sulpiride infusions within the perifornical region of the lateral hypothalamus enhance consolidation of associative learning. Psychopharmacology (Berl) 1998;140:354–364.
  73. Mehta MA, Hinton EC, Montgomery AJ, Bantick RA, Grasby PM: 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 2005;19:29–38.
  74. Eyny YS, Horvitz JC: Opposing roles of D1 and D2 receptors in appetitive conditioning. J Neurosci 2003;23:1584–1587.
  75. Smith-Roe SL, Kelley AE: Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning. J Neurosci 2000;20:7737–7742.
  76. Reynolds JN, Wickens JR: Dopamine-dependent plasticity of corticostriatal synapses. Neural Netw 2002;15:507–521.
  77. Calabresi P, Gubellini P, Centonze D, Picconi B, Bernardi G, Chergui K, Svenningsson P, Fienberg AA, Greengard P: Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation, opposing forms of synaptic plasticity. J Neurosci 2000;20:8443–8451.
  78. Gurden H, Takita M, Jay TM: Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J Neurosci 2000;20:RC106.
  79. Xu TX, Yao WD: D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex. Proc Natl Acad Sci USA 2010;107:16366–16371.
  80. Morein-Zamir S, Craig KJ, Ersche KD, Abbott S, Muller U, Fineberg NA, Bullmore ET, Sahakian BJ, Robbins TW: Impaired visuospatial associative memory and attention in obsessive compulsive disorder but no evidence for differential dopaminergic modulation. Psychopharmacology (Berl) 2010;212:357–367.


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