The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics. 1. Introduction An association between neurodegeneration of the dopaminergic nigrostriatal system and the major motor symptoms of Parkinson’s disease (PD) was first recognized in 1960 [1] after pioneering work by Arvid Carlsson showed that L-DOPA reversed the parkinsonian syndrome in rabbits induced by reserpine [2]. This observation led to the first trials of injected levodopa (L-dopa), a direct metabolic precursor of dopamine, to address motor symptoms associated with the disease. This treatment demonstrated transient success, but was impractical due to severe toxicities associated with the injections. Gradual titration of oral L-dopa was better tolerated, but was still associated with severe nausea and the requirement of higher doses of L-dopa due to peripheral consumption of the substrate. In the 1970s, compounding L-dopa with the peripheral dopa-decarboxylase inhibitor carbidopa very successfully addressed these shortcomings. Nausea and vomiting were reduced to such a degree that the medication adopted the trade name Sinemet (sine？=？without; emet = emesis). Compounded levodopa-carbidopa remains the mainstay of treatment for PD. Dopaminergic agonists are synthetic analogues of dopamine. Apomorphine was suggested for the treatment of PD as early as 1884 [3], although the first article describing its effectiveness was not published until 1951 [4]. Bromocriptine was found to be effective in PD in 1974 [5]. Other
References
[1]
H. Ehringer and O. Hornykiewicz, “Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system,” Klinische Wochenschrift, vol. 38, pp. 1236–1239, 1960.
[2]
A. Carlsson, M. Lindqvist, and T. Magnusson, “3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists,” Nature, vol. 180, no. 4596, p. 1200, 1957.
[3]
E. Weill, “De l’apomorphine dans certains troubles nerveux,” Lyon Med, vol. 48, pp. 411–419, 1884.
[4]
R. S. Schwab, L. V. Amador, and J. Y. Lettvin, “Apomorphine in Parkinson's disease,” Transactions of the American Neurological Association, vol. 56, pp. 251–253, 1951.
[5]
D. B. Calne, P. F. Teychenne, L. E. Claveria, et al., “Bromocriptine in Parkinsonism,” British Medical Journal, vol. 4, no. 5942, pp. 442–444, 1974.
[6]
V. Voon, P. O. Fernagut, J. Wickens et al., “Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders,” The Lancet Neurology, vol. 8, no. 12, pp. 1140–1149, 2009.
[7]
S. Y. Lim, A. H. Evans, and J. M. Miyasaki, “Impulse control and related disorders in Parkinson's disease: review,” Annals of the New York Academy of Sciences, vol. 1142, pp. 85–107, 2008.
[8]
P. Sokoloff, B. Giros, M. P. Martres, M. L. Bouthenet, and J. C. Schwartz, “Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics,” Nature, vol. 347, no. 6289, pp. 146–151, 1990.
[9]
M. Gerlach, K. Double, T. Arzberger, F. Leblhuber, T. Tatschner, and P. Riederer, “Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum,” Journal of Neural Transmission, vol. 110, no. 10, pp. 1119–1127, 2003.
[10]
S. Perachon, J. C. Schwartz, and P. Sokoloff, “Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors,” European Journal of Pharmacology, vol. 366, no. 2-3, pp. 293–300, 1999.
[11]
M. F. Piercey, “Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson's disease,” Clinical Neuropharmacology, vol. 21, no. 3, pp. 141–151, 1998.
[12]
E. V. Gurevich and J. N. Joyce, “Distribution of dopamine D3 receptor expressing neurons in the human forebrain comparison with D2 receptor expressing neurons,” Neuropsychopharmacology, vol. 20, no. 1, pp. 60–80, 1999.
[13]
P. Sokoloff, J. Diaz, B. Le Foll et al., “The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders,” Current Drug Targets-CNS & Neurological Disorders, vol. 5, no. 1, pp. 25–43, 2006.
[14]
M. Pilla, S. Perachon, F. Sautel et al., “Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist,” Nature, vol. 400, no. 6742, pp. 371–375, 1999.
[15]
D. Acilli, C. S. Fishburn, J. Drago et al., “A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 5, pp. 1945–1949, 1996.
[16]
J. L. Montastruc, L. Schmitt, and H. Bagheri, “Pathological gambling behavior in a patient with Parkinson's disease treated with levodopa and bromocriptine,” Revue Neurologique, vol. 159, no. 4, pp. 441–443, 2003.
[17]
C. Guigoni, I. Aubert, Q. Li et al., “Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors,” Parkinsonism and Related Disorders, vol. 11, supplement 1, pp. S25–S29, 2005.
[18]
N. P. Visanji, S. H. Fox, T. Johnston, G. Reyes, M. J. Millan, and J. M. Brotchie, “Dopamine D3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson's disease,” Neurobiology of Disease, vol. 35, no. 2, pp. 184–192, 2009.
[19]
D. A. Gallagher, S. S. O'Sullivan, A. H. Evans, A. J. Lees, and A. Schrag, “Pathological gambling in Parkinson's disease: risk factors and differences from dopamine dysregulation. An analysis of published case series,” Movement Disorders, vol. 22, no. 12, pp. 1757–1763, 2007.
[20]
D. Weintraub, J. Koester, M. N. Potenza et al., “Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients,” Archives of Neurology, vol. 67, no. 5, pp. 589–595, 2010.
[21]
A. Hassan, J. H. Bower, N. Kumar et al., “Dopamine agonist-triggered pathological behaviors: surveillance in the PD clinic reveals high frequencies,” Parkinsonism and Related Disorders, vol. 17, no. 4, pp. 260–264, 2011.
[22]
J. M. Bostwick, K. A. Hecksel, S. R. Stevens, J. H. Bower, and J. E. Ahlskog, “Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease,” Mayo Clinic Proceedings, vol. 84, no. 4, pp. 310–316, 2009.
[23]
G. D'Orsi, V. Demaio, and L. M. Specchio, “Pathological gambling plus hypersexuality in restless legs syndrome: a new case,” Neurological Sciences, vol. 32, no. 4, pp. 707–709, 2011.
[24]
P. Demetriades, H. Rickards, and A. E. Cavanna, “Impulse control disorders following deep brain stimulation of the subthalamic nucleus in Parkinson's disease: clinical aspects,” Parkinson's Disease, vol. 2011, Article ID 658415, 9 pages, 2011.
[25]
M. Broen, A. Duits, V. Visser-Vandewalle, Y. Temel, and A. Winogrodzka, “Impulse control and related disorders in Parkinson's disease patients treated with bilateral subthalamic nucleus stimulation: a review,” Parkinsonism and Related Disorders, vol. 17, no. 6, pp. 413–417, 2011.
[26]
C. Ardouin, V. Voon, Y. Worbe et al., “Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation,” Movement Disorders, vol. 21, no. 11, pp. 1941–1946, 2006.
[27]
T. Witjas, C. Baunez, J. M. Henry et al., “Addiction in Parkinson's disease: impact of subthalamic nucleus deep brain stimulation,” Movement Disorders, vol. 20, no. 8, pp. 1052–1055, 2005.
[28]
F. Bandini, A. Primavera, M. Pizzorno, and L. Cocito, “Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson's disease,” Parkinsonism and Related Disorders, vol. 13, no. 6, pp. 369–371, 2007.
[29]
D. Knobel, S. Aybek, C. Pollo, F. J. G. Vingerhoets, and A. Berney, “Rapid resolution of dopamine dysregulation syndrome (DDS) after subthalamic DBS for Parkinson disease (PD): a case report,” Cognitive and Behavioral Neurology, vol. 21, no. 3, pp. 187–189, 2008.
[30]
H. M. Smeding, A. E. Goudriaan, E. M. Foncke, P. R. Schuurman, J. D. Speelman, and B. Schmand, “Pathological gambling after bilateral subthalamic nucleus stimulation in Parkinson disease,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 5, pp. 517–519, 2007.
[31]
T. D. H？lbig, W. Tse, P. G. Frisina et al., “Subthalamic deep brain stimulation and impulse control in Parkinson's disease,” European Journal of Neurology, vol. 16, no. 4, pp. 493–497, 2009.
[32]
S. Y. Lim, S. S. O'Sullivan, K. Kotschet et al., “Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease,” Journal of Clinical Neuroscience, vol. 16, no. 9, pp. 1148–1152, 2009.
[33]
M. J. Frank, “Hold your horses: a dynamic computational role for the subthalamic nucleus in decision making,” Neural Networks, vol. 19, no. 8, pp. 1120–1136, 2006.
[34]
M. J. Frank, J. Samanta, A. A. Moustafa, and S. J. Sherman, “Hold your horses: impulsivity, deep brain stimulation, and medication in Parkinsonism,” Science, vol. 318, no. 5854, pp. 1309–1312, 2007.
[35]
E. Mamikonyan, A. D. Siderowf, J. E. Duda et al., “Long-term follow-up of impulse control disorders in Parkinson's disease,” Movement Disorders, vol. 23, no. 1, pp. 75–80, 2008.
[36]
A. Bharmal, C. Lu, J. Quickfall, D. Crockford, and O. Suchowersky, “Outcomes of patients with Parkinson disease and pathological gambling,” The Canadian Journal of Neurological Sciences, vol. 37, no. 4, pp. 473–477, 2010.
[37]
M. L. Dodd, K. J. Klos, J. H. Bower, Y. E. Geda, K. A. Josephs, and J. E. Ahlskog, “Pathological gambling caused by drugs used to treat Parkinson disease,” Archives of Neurology, vol. 62, no. 9, pp. 1377–1381, 2005.
[38]
V. Voon, J. Gao, C. Brezing et al., “Dopamine agonists and risk: impulse control disorders in Parkinson's; disease,” Brain, vol. 134, no. 5, pp. 1438–1446, 2011.
[39]
J. Reuter, T. Raedler, M. Rose, I. Hand, J. Gl？scher, and C. Büchel, “Pathological gambling is linked to reduced activation of the mesolimbic reward system,” Nature Neuroscience, vol. 8, no. 2, pp. 147–148, 2005.
[40]
H. Rao, M. Korczykowski, J. Pluta, A. Hoang, and J. A. Detre, “Neural correlates of voluntary and involuntary risk taking in the human brain: an fMRI study of the balloon analog risk task (BART),” NeuroImage, vol. 42, no. 2, pp. 902–910, 2008.
[41]
T. D. Steeves, J. Miyasaki, M. Zurowski et al., “Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study,” Brain, vol. 132, no. 5, pp. 1376–1385, 2009.
[42]
T. Van Eimeren, G. Pellecchia, R. Cilia et al., “Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD,” Neurology, vol. 75, no. 19, pp. 1711–1716, 2010.
[43]
D. Kahnemann and A. Tversky, “Prospect theory: an analysis of decision under risk,” in Choices, Values and Frames, D. Kahnemann and A. Tversky, Eds., Cambridge University Press, New York, NY, USA, 2000.
[44]
D. Kapogiannis, E. Mooshagian, P. Campion et al., “Reward processing abnormalities in Parkinson's disease,” Movement Disorders, vol. 26, no. 8, pp. 1451–1457, 2011.
[45]
M. H. Bloch, B. S. Peterson, L. Scahill et al., “Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome,” Archives of Pediatrics and Adolescent Medicine, vol. 160, no. 1, pp. 65–69, 2006.
[46]
T. D. Steeves, J. H. Ko, D. M. Kideckel et al., “Extrastriatal dopaminergic dysfunction in Tourette syndrome,” Annals of Neurology, vol. 67, no. 2, pp. 170–181, 2010.
[47]
L. De Carolis, C. Schepisi, M. S. Milella, and P. Nencini, “Clomipramine, but not haloperidol or aripiprazole, inhibits quinpirole-induced water contrafreeloading, a putative animal model of compulsive behavior,” Psychopharmacology, vol. 218, no. 4, pp. 749–759, 2011.
[48]
D. Kontis, V. Boulougouris, V. M. Papakosta et al., “Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive-compulsive disorder,” Psychopharmacology, vol. 200, no. 4, pp. 597–610, 2008.
[49]
C. Achat-Mendes, P. Grundt, J. Cao, D. M. Platt, A. H. Newman, and R. D. Spealman, “Dopamine D3 and D2 receptor mechanisms in the abuse-related behavioral effects of cocaine: studies with preferential antagonists in squirrel monkeys,” Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 2, pp. 556–565, 2010.
[50]
K. J. Thiel, J. M. Wenzel, N. S. Pentkowski, R. J. Hobbs, A. T. Alleweireldt, and J. L. Neisewander, “Stimulation of dopamine D2/D3 but not D1 receptors in the central amygdala decreases cocaine-seeking behavior,” Behavioural Brain Research, vol. 214, no. 2, pp. 386–394, 2010.
[51]
R. Bordet, S. Ridray, S. Carboni, J. Diaz, P. Sokoloff, and J. C. Schwartz, “Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 7, pp. 3363–3367, 1997.
[52]
E. Bézard, S. Ferry, U. Mach et al., “Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function,” Nature Medicine, vol. 9, no. 6, pp. 762–767, 2003.
