Abstract
Rationale
Impulse control disorders (ICD) and other impulsive-compulsive behaviours are frequently found in Parkinson’s disease (PD) patients treated with dopaminergic agonists. To date, there are no available animal models to investigate their pathophysiology and determine whether they can be elicited by varying doses of dopaminergic drugs. In addition, there is some controversy regarding the predispositional pattern of striatal dopaminergic depletion.
Objectives
To study the effect of two doses of pramipexole (PPX) on motor impulsivity, delay intolerance and compulsive-like behaviour.
Methods
Male rats with mild dopaminergic denervation in the dorsolateral striatum (bilateral injections of 6-hydroxidopamine (6-OHDA)) treated with two doses of PPX (0.25 mg/kg and 3 mg/kg) and tested in the variable delay-to-signal paradigm.
Results
Partial (50%) dopaminergic depletion did not induce significant changes in motor impulsivity or delay intolerance. However, 0.25 mg/kg of PPX increased motor impulsivity, while 3 mg/kg of PPX increased both motor impulsivity and delay intolerance. These effects were independent of the drug’s antiparkinsonian effects. Importantly, impulsivity scores before and after dopaminergic lesion were positively associated with the impulsivity observed after administering 3 mg/kg of PPX. No compulsive-like behaviour was induced by PPX administration.
Conclusions
We described a rat model, with a moderate dorsolateral dopaminergic lesion resembling that suffered by patients with early PD, that develops different types of impulsivity in a dose-dependent manner dissociated from motor benefits when treated with PPX. This model recapitulates key features of abnormal impulsivity in PD and may be useful for deepening our understanding of the pathophysiology of ICD.
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Change history
03 July 2020
In the original version of this article, the Figure 3 was published in an incorrect format, even though the data and the related information in the text are correct.
References
Aguirre M, Couderc A, Epinat-Duclos J, Mascaro O (2019) Infants discriminate the source of social touch at stroking speeds eliciting maximal firing rates in CT-fibers. Dev Cogn Neurosci 36:100639. https://doi.org/10.1016/j.dcn.2019.100639
Al-Khaled M, Heldmann M, Bolstorff I et al (2015) Intertemporal choice in Parkinson’s disease and restless legs syndrome. Parkinsonism Relat Disord 21:1330–1335. https://doi.org/10.1016/j.parkreldis.2015.09.026
Antonelli F, Ko JH, Miyasaki J, Lang AE, Houle S, Valzania F, Ray NJ, Strafella AP (2014) Dopamine-agonists and impulsivity in Parkinson’s disease: Impulsive choices vs. impulsive actions. Hum Brain Mapp 35:2499–2506. https://doi.org/10.1002/hbm.22344
Ballivet J, Marin A, Gisselmann A (1973) Aspects of hypersexuality observed in parkinsonian patients treated by L-dopa. Ann Med Psychol (Paris) 2:515–522
Barbosa PM, Grippe T, Lees AJ et al (2018) Compulsive sexual behaviour in Parkinson’s disease is associated with higher doses of levodopa. J. Neurol. Neurosurg. Psychiatry 89:1121–1123
Bari A, Robbins TW (2013) Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol 108:44–79
Bastiaens J, Dorfman BJ, Christos PJ, Nirenberg MJ (2013) Prospective cohort study of impulse control disorders in Parkinson’s disease. Mov Disord 28:327–333. https://doi.org/10.1002/mds.25291
Bido S, Soria FN, Fan RZ, Bezard E, Tieu K (2017) Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease. Sci Rep 7:7495. https://doi.org/10.1038/s41598-017-07181-0
Canário N, Sousa M, Moreira F, Duarte IC, Oliveira F, Januário C, Castelo-Branco M (2019) Impulsivity across reactive, proactive and cognitive domains in Parkinson’s disease on dopaminergic medication: evidence for multiple domain impairment. PLoS One 14:e0210880. https://doi.org/10.1371/journal.pone.0210880
Carvalho MM, Campos FL, Marques M, Soares-Cunha C, Kokras N, Dalla C, Leite-Almeida H, Sousa N, Salgado AJ (2017) Effect of levodopa on reward and impulsivity in a rat model of Parkinson’s disease. Front Behav Neurosci 11:145. https://doi.org/10.3389/fnbeh.2017.00145
Cenci MA, Francardo V, O’Sullivan SS, Lindgren HS (2015) Rodent models of impulsive-compulsive behaviors in Parkinson’s disease: how far have we reached? Neurobiol Dis 82:561–573
Cilia R, Ko JH, Cho SS, van Eimeren T, Marotta G, Pellecchia G, Pezzoli G, Antonini A, Strafella AP (2010) Reduced dopamine transporter density in the ventral striatum of patients with Parkinson’s disease and pathological gambling. Neurobiol Dis 39:98–104. https://doi.org/10.1016/j.nbd.2010.03.013
Cornelius JR, Tippmann-Peikert M, Slocumb NL et al (2010) Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep 33:81–87. https://doi.org/10.1016/j.yneu.2010.12.010
Corvol J-C, Artaud F, Cormier-Dequaire F, Rascol O, Durif F, Derkinderen P, Marques AR, Bourdain F, Brandel JP, Pico F, Lacomblez L, Bonnet C, Brefel-Courbon C, Ory-Magne F, Grabli D, Klebe S, Mangone G, You H, Mesnage V, Lee PC, Brice A, Vidailhet M, Elbaz A, For the DIGPD Study Group (2018) Longitudinal analysis of impulse control disorders in Parkinson disease. Neurology 91:e189–e201. https://doi.org/10.1212/wnl.0000000000005816
Cossu G, Rinaldi R, Colosimo C (2018) The rise and fall of impulse control behavior disorders. Parkinsonism Relat Disord 46:S24–S29. https://doi.org/10.1016/j.parkreldis.2017.07.030
Dalley JW, Robbins TW (2017) Fractionating impulsivity: neuropsychiatric implications. Nat Rev Neurosci 18:158–171
Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity, and top-down cognitive control. Neuron 69:680–694
Dardou D, Reyrolle L, Chassain C, Durif F (2017) Chronic pramipexole treatment induces compulsive behavior in rats with 6-OHDA lesions of the substantia nigra and ventral tegmental area. Behav Brain Res 332:327–336. https://doi.org/10.1016/j.bbr.2017.06.016
De Micco R, Russo A, Tedeschi G, Tessitore A (2018) Impulse control behaviors in Parkinson’s disease: drugs or disease? Contribution from imaging studies. Front Neurol 9:893. https://doi.org/10.3389/fneur.2018.00893
Engeln M, Ahmed SH, Vouillac C, Tison F, Bezard E, Fernagut PO (2013) Reinforcing properties of Pramipexole in normal and parkinsonian rats. Neurobiol Dis 49:79–86. https://doi.org/10.1016/j.nbd.2012.08.005
Engeln M, Ansquer S, Dugast E, Bezard E, Belin D, Fernagut PO (2016) Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy. Neuropharmacology 109:69–77. https://doi.org/10.1016/j.neuropharm.2016.05.013
Fabbrini G, Brotchie JM, Grandas F et al (2007) Levodopa-induced dyskinesias. Mov Disord 22:1379–1389
Gago B, Marin C, Rodríguez-Oroz MC, Obeso JA (2013) L-dopa-induced dyskinesias in unilateral 6-hydroxydopamine-lesioned rats are not modified by excitotoxic lesion of the entopeduncular nucleus and substantia nigra pars reticulata. Synapse 67:407–414. https://doi.org/10.1002/syn.21652
Gillies A, Arbuthnott G (2000) Pathologic gambling in Parkinson’s disease: a behavioral manifestation of pharmacologic treatment? Mov Disord 15:869–872. https://doi.org/10.1002/1531-8257(200009)15:5<869::AID-MDS1016>3.0.CO;2-I
Holman AJ (2009) Impulse control disorder behaviors associated with pramipexole used to treat fibromyalgia. J Gambl Stud 25:425–431. https://doi.org/10.1007/s10899-009-9123-2
Holtz NA, Tedford SE, Persons AL, Grasso SA, Napier TC (2016) Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson’s disease. Prog Neuro-Psychopharmacology Biol Psychiatry 70:77–84. https://doi.org/10.1016/j.pnpbp.2016.05.004
Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson’s disease. Adv Neurol 45:19–34
Houeto JL, Magnard R, Dalley JW, Belin D, Carnicella S (2016) Trait impulsivity and anhedonia: two gateways for the development of impulse control disorders in Parkinson’s disease? Front Psychiatry 7:91. https://doi.org/10.3389/fpsyt.2016.00091
Housden CR, O’Sullivan SS, Joyce EM et al (2010) Intact reward learning but elevated delay discounting in Parkinson’s disease patients with impulsive-compulsive spectrum behaviors. Neuropsychopharmacology 35:2155–2164. https://doi.org/10.1038/npp.2010.84
Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376
Jenner P (2015) Treatment of the later stages of Parkinson’s disease - pharmacological approaches now and in the future. Transl Neurodegener 4
Jiménez-Urbieta H, Gago B, de la Riva P et al (2015) Dyskinesias and impulse control disorders in Parkinson’s disease: from pathogenesis to potential therapeutic approaches. Neurosci Biobehav Rev 56:294–314
Jiménez-Urbieta H, Gago B, Quiroga-Varela A, Rodríguez-Chinchilla T, Merino-Galán L, Oregi A, Belloso-Iguerategui A, Delgado-Alvarado M, Navalpotro-Gómez I, Marin C, Fernagut PO, Rodríguez-Oroz MC (2019) Pramipexole-induced impulsivity in mildparkinsonian rats: a model of impulse control disorders in Parkinson’s disease. Neurobiol Aging 75:126–135. https://doi.org/10.1016/j.neurobiolaging.2018.11.021
Joutsa J, Voon V, Johansson J, Niemelä S, Bergman J, Kaasinen V (2015) Dopaminergic function and intertemporal choice. Transl Psychiatry 5. https://doi.org/10.1038/tp.2014.133
Kim BS, Im HI (2019) The role of the dorsal striatum in choice impulsivity. Ann N Y Acad Sci 1451:92–111
Leite-Almeida H, Melo A, Pêgo JM, Bernardo S, Milhazes N, Borges F, Sousa N, Almeida A, Cerqueira JJ (2013) Variable delay-to-signal: a fast paradigm for assessment of aspects of impulsivity in rats. Front Behav Neurosci 7:154. https://doi.org/10.3389/fnbeh.2013.00154
Leroi I, Barraclough M, McKie S, Hinvest N, Evans J, Elliott R, McDonald K (2013) Dopaminergic influences on executive function and impulsive behaviour in impulse control disorders in Parkinson’s disease. J Neuropsychol 7:306–325. https://doi.org/10.1111/jnp.12026
Magnard R, Vachez Y, Carcenac C, Boulet S, Houeto JL, Savasta M, Belin D, Carnicella S (2018) Nigrostriatal dopaminergic denervation does not promote impulsive choice in the rat: implication for impulse control disorders in Parkinson’s disease. Front Behav Neurosci 12:312. https://doi.org/10.3389/fnbeh.2018.00312
Maj J, Rogóz Z, Skuza G, Kołodziejczyk K (1997) The behavioural effects of pramipexole, a novel dopamine receptor agonist. Eur J Pharmacol 324:31–37. https://doi.org/10.1016/S0014-2999(97)00066-6
Maloney EM, Djamshidian A, O’Sullivan SS (2017) Phenomenology and epidemiology of impulsive-compulsive behaviours in Parkinson’s disease, atypical Parkinsonian disorders and non-Parkinsonian populations. J Neurol Sci 374:47–52
Martini A, Dal Lago D, Edelstyn NMJ, Salgarello M, Lugoboni F, Tamburin S (2018) Dopaminergic neurotransmission in patients with Parkinson’s Disease and impulse control disorders: a systematic review and meta-analysis of PET and SPECT studies. Front Neurol 9:1018. https://doi.org/10.3389/fneur.2018.01018
Meyer GM, Spay C, Laurencin C, Ballanger B, Sescousse G, Boulinguez P (2019) Functional imaging studies of Impulse Control Disorders in Parkinson’s disease need a stronger neurocognitive footing. Neurosci Biobehav Rev 98:164–176
Milenkova M, Mohammadi B, Kollewe K, Schrader C, Fellbrich A, Wittfoth M, Dengler R, Münte TF (2011) Intertemporal choice in Parkinson’s disease. Mov Disord 26:2004–2010. https://doi.org/10.1002/mds.23756
Navalpotro-Gomez I, Dacosta-Aguayo R, Molinet-Dronda F, Martin-Bastida A, Botas-Peñin A, Jimenez-Urbieta H, Delgado-Alvarado M, Gago B, Quiroga-Varela A, Rodriguez-Oroz MC (2019) Nigrostriatal dopamine transporter availability, and its metabolic and clinical correlates in Parkinson’s disease patients with impulse control disorders. Eur J Nucl Med Mol Imaging 46:2065–2076. https://doi.org/10.1007/s00259-019-04396-3
Nombela C, Rittman T, Robbins TW, Rowe JB (2014) Multiple modes of impulsivity in parkinson’s disease. PLoS One 9:e85747. https://doi.org/10.1371/journal.pone.0085747
Obeso I, Wilkinson L, Casabona E, Bringas ML, Álvarez M, Álvarez L, Pavón N, Rodríguez-Oroz MC, Macías R, Obeso JA, Jahanshahi M (2011) Deficits in inhibitory control and conflict resolution on cognitive and motor tasks in Parkinson’s disease. Exp Brain Res 212:371–384. https://doi.org/10.1007/s00221-011-2736-6
Premi E, Pilotto A, Garibotto V, Bigni B, Turrone R, Alberici A, Cottini E, Poli L, Bianchi M, Formenti A, Cosseddu M, Gazzina S, Magoni M, Bertoli M, Paghera B, Borroni B, Padovani A (2016) Impulse control disorder in PD: a lateralized monoaminergic frontostriatal disconnection syndrome? Parkinsonism Relat Disord 30:62–66. https://doi.org/10.1016/j.parkreldis.2016.05.028
Quiroga-Varela A, Aguilar E, Iglesias E, Obeso JA, Marin C (2017) Short- and long-term effects induced by repeated 6-OHDA intraventricular administration: a new progressive and bilateral rodent model of Parkinson’s disease. Neuroscience 361:144–156. https://doi.org/10.1016/j.neuroscience.2017.08.017
R Core Team (2017) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/
Rokosik SL, Napier TC (2012) Pramipexole-induced increased probabilistic discounting: comparison between a rodent model of parkinson’s disease and controls. Neuropsychopharmacology 37:1397–1408. https://doi.org/10.1038/npp.2011.325
Schulz P, Labudda K, Bertke V, Bellgardt S, Boedeker S, Spannhorst S, Kreisel SH, Driessen M, Beblo T, Toepper M (2019) Age effects on traffic sign comprehension. IATSS Res. https://doi.org/10.1016/j.iatssr.2019.10.001
Smith KM, Xie SX, Weintraub D (2016) Incident impulse control disorder symptoms and dopamine transporter imaging in Parkinson disease. J Neurol Neurosurg Psychiatry 87:864–870. https://doi.org/10.1136/jnnp-2015-311827
Soares AR, Esteves M, Moreira PS, Cunha AM, Guimarães MR, Carvalho MM, Raposo-Lima C, Morgado P, Carvalho AF, Coimbra B, Melo A, Rodrigues AJ, Salgado AJ, Pêgo JM, Cerqueira JJ, Costa P, Sousa N, Almeida A, Leite-Almeida H (2018) Trait determinants of impulsive behavior: a comprehensive analysis of 188 rats. Sci Rep 8:17666. https://doi.org/10.1038/s41598-018-35537-7
Steeves TDL, Miyasaki J, Zurowski M, Lang AE, Pellecchia G, van Eimeren T, Rusjan P, Houle S, Strafella AP (2009) Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study. Brain 132:1376–1385. https://doi.org/10.1093/brain/awp054
Stowe RL, Ives NJ, Clarke C et al (2008) Dopamine agonist therapy in early Parkinson’s disease. Cochrane Database Syst Rev
Szamosi A, Nagy H, Kéri S (2012) Delay discounting of reward and caudate nucleus volume in individuals with α-synuclein gene duplication before and after the development of Parkinson’s disease. Neurodegener Dis 11:72–78. https://doi.org/10.1159/000341997
Tedford SE, Persons AL, Napier TC (2015) Dopaminergic lesions of the dorsolateral striatum in rats increase delay discounting in an impulsive choice task. PLoS One 10:e0122063. https://doi.org/10.1371/journal.pone.0122063
Tremblay M, Silveira MM, Kaur S, Hosking JG, Adams WK, Baunez C, Winstanley CA (2017) Chronic D2/3agonist ropinirole treatment increases preference for uncertainty in rats regardless of baseline choice patterns. Eur J Neurosci 45:159–166. https://doi.org/10.1111/ejn.13332
Villacorta PJ (2017) The welchADF package for robust hypothesis testing in unbalanced multivariate mixed models with heteroscedastic and non-normal data. R J 9:309–328. https://doi.org/10.32614/rj-2017-049
Voon V, Dalley JW (2016) Translatable and back-translatable measurement of impulsivity and compulsivity: convergent and divergent processes. Curr Top Behav Neurosci 28:53–91. https://doi.org/10.1007/7854_2015_5013
Voon V, Fox SH (2007) Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 64:1089–1096
Voon V, Reynolds B, Brezing C, Gallea C, Skaljic M, Ekanayake V, Fernandez H, Potenza MN, Dolan RJ, Hallett M (2010) Impulsive choice and response in dopamine agonist-related impulse control behaviors. Psychopharmacology 207:645–659. https://doi.org/10.1007/s00213-009-1697-y
Voon V, Mehta AR, Hallett M (2011) Impulse control disorders in Parkinson’s disease: recent advances. Curr Opin Neurol 24:324–330
Voon V, Napier TC, Frank MJ, Sgambato-Faure V, Grace AA, Rodriguez-Oroz M, Obeso J, Bezard E, Fernagut PO (2017) Impulse control disorders and levodopa-induced dyskinesias in Parkinson’s disease: an update. Lancet Neurol. 16:238–250
Vriend C, Nordbeck AH, Booij J, van der Werf YD, Pattij T, Voorn P, Raijmakers P, Foncke EMJ, van de Giessen E, Berendse HW, van den Heuvel OA (2014) Reduced dopamine transporter binding predates impulse control disorders in Parkinson’s disease. Mov Disord 29:904–911. https://doi.org/10.1002/mds.25886
Weintraub D, Claassen DO (2017) Impulse control and related disorders in Parkinson’s disease. Int. Rev. Neurobiol. 133:679–717
Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, Whetteckey J, Wunderlich GR, Lang AE (2010) Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 67:589–595. https://doi.org/10.1001/archneurol.2010.65
Weintraub D, David AS, Evans AH, Grant JE, Stacy M (2015) Clinical spectrum of impulse control disorders in Parkinson’s disease. Mov Disord 30:121–127
Funding
This work was supported by Diputación Foral de Guipuzcoa (DFG11/019), the Instituto de Salud Carlos III (ISCIII; PI11/02109), FEDER funds and CIBERNED. HJ-U and AB-I are funded by Basque Country Ph.D. Studentships. TR-C is funded by a CIBERNED Ph.D. Studentship and a Fundación Jesús Gangoiti Barrera grant. LM-G is funded by a Basque Country University Ph.D. Studentship.
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Experimental procedures were approved by the Committee on Animal Research and Ethics at Biodonostia Health Research Institute (Spain) in accordance with the guidelines of the Spanish Government (RD53/2013) and European Communities Council Directive (2010/63/EU).
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Jiménez-Urbieta, H., Gago, B., Quiroga-Varela, A. et al. Motor impulsivity and delay intolerance are elicited in a dose-dependent manner with a dopaminergic agonist in parkinsonian rats. Psychopharmacology 237, 2419–2431 (2020). https://doi.org/10.1007/s00213-020-05544-6
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DOI: https://doi.org/10.1007/s00213-020-05544-6