Abstract
Parkinson’s disease (PD), which is traditionally viewed as a motor disorder involving the degeneration of dopaminergic (DA) neurons, has recently been identified as a quintessential neuropsychiatric condition. Indeed, a plethora of non-motor symptoms may occur in PD, including apathy. Apathy can be defined as a lack of motivation or a deficit of goal-directed behaviors and results in a pathological decrease of self-initiated voluntary behavior. Apathy in PD appears to fluctuate with the DA state of the patients, suggesting a critical role of DA neurotransmission in the pathophysiology of this neuropsychiatric syndrome. Using a lesion-based approach, we developed a rodent model which exhibits specific alteration in the preparatory component of motivational processes, reminiscent to apathy in PD. We found a selective decrease of DA D3 receptors (D3R) expression in the dorsal striatum of lesioned rats. Next, we showed that inhibition of D3R neurotransmission in non-lesioned animals was sufficient to reproduce the motivational deficit observed in our model. Interestingly, we also found that pharmacologically targeting D3R efficiently reversed the motivational deficit induced by the lesion. Our findings, among other recent data, suggest a critical role of D3R in parkinsonian apathy and highlight this receptor as a promising target for treating motivational deficits.
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References
Aarsland D, Marsh L, Schrag A (2009a) Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord 24:2175–2186
Aarsland D, Bronnick K, Alves G et al (2009b) The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry 80:928–930
Agid Y, Ruberg M, Dubois B, Javoy-Agid F (1984) Biochemical substrates of mental disturbances in Parkinson’s disease. Adv Neurol 40:211–218
Beaulieu JM, Espinoza S, Gainetdinov RR (2015) Dopamine receptors - IUPHAR review 13. Br J Pharmacol 172:1–23
Belin D, Everitt BJ (2008) Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57:432–441
Belin D, Jonkman S, Dickinson A et al (2009) Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav Brain Res 199:89–102
Beninger RJ, Banasikowski TJ (2008) Dopaminergic mechanism of reward-related incentive learning: focus on the dopamine D(3) receptor. Neurotox Res 14:57–70
Beninger RJ, D'Amico CM, Ranaldi R (1993) Microinjections of flupenthixol into the caudate putamen of rats produce intrasession declines in food-rewarded operant responding. Pharmacol Biochem Behav 45:343–350
Berke JD (2018) What does dopamine mean? Nat Neurosci 21:787–793
Berridge KC (2007) The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology 191:391–431
Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28:309–369
Bezard E, Ferry S, Mach U et al (2003) Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 9:762–767
Bouthenet ML, Souil E, Martres MP et al (1991) Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res 564:203–219
Brizard M, Carcenac C, Bemelmans AP et al (2006) Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson’s disease. Neurobiol Dis 21:90–101
Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68:815–834
Brown RG, Pluck G (2000) Negative symptoms: the ‘pathology’ of motivation and goal-directed behaviour. Trends Neurosci 23:412–417
Carcenac C, Favier M, Vachez Y et al (2015) Subthalamic deep brain stimulation differently alters striatal dopaminergic receptor levels in rats. Mov Disord 30:1739–1749
Carnicella S, Drui G, Boulet S et al (2014) Implication of dopamine D3 receptor activation in the reversion of Parkinson’s disease-related motivational deficits. Transl Psychiatry 4:e401
Castrioto A, Thobois S, Carnicella S et al (2016) Emotional manifestations of PD: neurobiological basis. Mov Disord 31:1103–1113
Chaudhuri A, Behan PO (2004) Fatigue in neurological disorders. Lancet 363:978–988
Chaudhuri KR, Schapira AH (2009) Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol 8:464–474
Chaudhuri KR, Healy DG, Schapira AH, National Institute for Clinical Excellence (2006) Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 5:235–245
Corbit LH, Janak PH (2007) Inactivation of the lateral but not medial dorsal striatum eliminates the excitatory impact of Pavlovian stimuli on instrumental responding. J Neurosci 27:13977–13981
Czernecki V, Pillon B, Houeto JL et al (2002) Motivation, reward, and Parkinson’s disease: influence of dopatherapy. Neuropsychologia 40:2257–2267
Czernecki V, Schupbach M, Yaici S et al (2008) Apathy following subthalamic stimulation in Parkinson disease: a dopamine responsive symptom. Mov Disord 23:964–969
da Silva JA, Tecuapetla F, Paixao V, Costa RM (2018) Dopamine neuron activity before action initiation gates and invigorates future movements. Nature 554:244–248
Deniau JM, Degos B, Bosch C, Maurice N (2010) Deep brain stimulation mechanisms: beyond the concept of local functional inhibition. Eur J Neurosci 32:1080–1091
Der-Avakian A, Markou A (2012) The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci 35:68–77
Drapier D, Drapier S, Sauleau P et al (2006) Does subthalamic nucleus stimulation induce apathy in Parkinson’s disease? J Neurol 253:1083–1091
Drijgers RL, Verhey FR, Tissingh G et al (2012) The role of the dopaminergic system in mood, motivation and cognition in Parkinson’s disease: a double blind randomized placebo-controlled experimental challenge with pramipexole and methylphenidate. J Neurol Sci 320:121–126
Drui G, Carnicella S, Carcenac C et al (2014) Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson’s disease. Mol Psychiatry 19:358–367
Dujardin K, Sockeel P, Delliaux M et al (2008) The Lille apathy rating scale: validation of a caregiver-based version. Mov Disord 23:845–849
Dujardin K, Langlois C, Plomhause L et al (2014) Apathy in untreated early-stage Parkinson disease: relationship with other non-motor symptoms. Mov Disord 29:1796–1801
Favier M, Duran T, Carcenac C et al (2014) Pramipexole reverses Parkinson’s disease-related motivational deficits in rats. Mov Disord 29:912–920
Favier M, Carcenac C, Savasta M, Carnicella S (2017) Motivation and apathy in Parkinson’s disease: implication of dopaminergic D3 receptors. Med Sci (Paris) 33:822–824
Fox SH, Lang AE (2008) Levodopa-related motor complications--phenomenology. Mov Disord 23(Suppl 3):S509–S514
Guillin O, Diaz J, Carroll P et al (2001) BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411:86–89
Houeto JL, Mesnage V, Mallet L et al (2002) Behavioural disorders, Parkinson’s disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry 72:701–707
Howe MW, Dombeck DA (2016) Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 535:505–510
Howe MW, Tierney PL, Sandberg SG et al (2013) Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature 500:575–579
Hurley MJ, Jenner P (2006) What has been learnt from study of dopamine receptors in Parkinson’s disease? Pharmacol Ther 111:715–728
Ilango A, Kesner AJ, Keller KL et al (2014) Similar roles of substantia nigra and ventral tegmental dopamine neurons in reward and aversion. J Neurosci 34:817–822
Isella V, Melzi P, Grimaldi M et al (2002) Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson’s disease. Mov Disord 17:366–371
Ishizaki J, Mimura M (2011) Dysthymia and apathy: diagnosis and treatment. Depress Res Treat 2011:893905
Jeanblanc J, He DY, McGough NN et al (2006) The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J Neurosci 26:1457–1464
Keiflin R, Pribut HJ, Shah NB, Janak PH (2019) Ventral tegmental dopamine neurons participate in reward identity predictions. Curr Biol 29:93–103.e3
Kirik D, Rosenblad C, Bjorklund A (1998) Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 152:259–277
Kirsch-Darrow L, Zahodne LB, Marsiske M et al (2011) The trajectory of apathy after deep brain stimulation: from pre-surgery to 6 months post-surgery in Parkinson’s disease. Parkinsonism Relat Disord 17:182–188
Kish SJ, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implications. N Engl J Med 318:876–880
Krack P, Hariz MI, Baunez C et al (2010) Deep brain stimulation: from neurology to psychiatry? Trends Neurosci 33:474–484
Kulagowski JJ, Broughton HB, Curtis NR et al (1996) 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J Med Chem 39:1941–1942
Kung MP, Chumpradit S, Frederick D et al (1994) Characterization of binding sites for [125I]R(+)trans-7-OH-PIPAT in rat brain. Naunyn Schmiedeberg’s Arch Pharmacol 350:611–617
Le Foll B, Goldberg SR, Sokoloff P (2005) The dopamine D3 receptor and drug dependence: effects on reward or beyond? Neuropharmacology 49:525–541
Le Jeune F, Drapier D, Bourguignon A et al (2009) Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study. Neurology 73:1746–1751
Le Moal M, Simon H (1991) Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiol Rev 71:155–234
Leentjens AF, Koester J, Fruh B et al (2009) The effect of pramipexole on mood and motivational symptoms in Parkinson’s disease: a meta-analysis of placebo-controlled studies. Clin Ther 31:89–98
Levesque D, Diaz J, Pilon C et al (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci U S A 89:8155–8159
Levy R, Dubois B (2006) Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex 16:916–928
Lhommee E, Klinger H, Thobois S et al (2012) Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviours. Brain 135:1463–1477
Loas G, Krystkowiak P, Godefroy O (2012) Anhedonia in Parkinson’s disease: an overview. J Neuropsychiatry Clin Neurosci 24:444–451
Magnard R, Vachez Y, Carcenac C et al (2016) What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson’s disease? Transl Psychiatry 6:e753
Marin RS (1990) Differential diagnosis and classification of apathy. Am J Psychiatry 147:22–30
Marin RS (1991) Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3:243–254
Marin RS, Biedrzycki RC, Firinciogullari S (1991) Reliability and validity of the apathy evaluation scale. Psychiatry Res 38:143–162
McGinty VB, Lardeux S, Taha SA et al (2013) Invigoration of reward seeking by cue and proximity encoding in the nucleus accumbens. Neuron 78:910–922
Mingote S, Weber SM, Ishiwari K et al (2005) Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions. Eur J Neurosci 21:1749–1757
Moraga-Amaro R, Gonzalez H, Pacheco R, Stehberg J (2014) Dopamine receptor D3 deficiency results in chronic depression and anxiety. Behav Brain Res 274:186–193
Morissette M, Goulet M, Grondin R et al (1998) Associative and limbic regions of monkey striatum express high levels of dopamine D3 receptors: effects of MPTP and dopamine agonist replacement therapies. Eur J Neurosci 10:2565–2573
Nieoullon A, Coquerel A (2003) Dopamine: a key regulator to adapt action, emotion, motivation and cognition. Curr Opin Neurol 16(Suppl 2):S3–S9
Nissenbaum H, Quinn NP, Brown RG et al (1987) Mood swings associated with the ‘on-off’ phenomenon in Parkinson’s disease. Psychol Med 17:899–904
Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P (2015) Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol 14:518–531
Palmiter RD (2008) Dopamine signaling in the dorsal striatum is essential for motivated behaviors: lessons from dopamine-deficient mice. Ann N Y Acad Sci 1129:35–46
Pecina S, Berridge KC (2013) Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue-triggered ‘wanting’ for reward: entire core and medial shell mapped as substrates for PIT enhancement. Eur J Neurosci 37:1529–1540
Pedersen KF, Larsen JP, Alves G, Aarsland D (2009) Prevalence and clinical correlates of apathy in Parkinson’s disease: a community-based study. Parkinsonism Relat Disord 15:295–299
Poewe W (2008) Non-motor symptoms in Parkinson’s disease. Eur J Neurol 15(Suppl 1):14–20
Rangel-Barajas C, Coronel I, Floran B (2015) Dopamine receptors and neurodegeneration. Aging Dis 6:349–368
Remy P, Doder M, Lees A et al (2005) Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128:1314–1322
Rossi MA, Sukharnikova T, Hayrapetyan VY et al (2013) Operant self-stimulation of dopamine neurons in the substantia nigra. PLoS One 8:e65799
Salamone JD, Correa M, Mingote S, Weber SM (2003) Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry, and drug abuse. J Pharmacol Exp Ther 305:1–8
Salamone JD, Pardo M, Yohn SE et al (2016) Mesolimbic dopamine and the regulation of motivated behavior. Curr Top Behav Neurosci 27:231–257
Samii A, Nutt JG, Ransom BR (2004) Parkinson’s disease. Lancet 363:1783–1793
Schmidt L, d'Arc BF, Lafargue G et al (2008) Disconnecting force from money: effects of basal ganglia damage on incentive motivation. Brain 131:1303–1310
Shiba M, Bower JH, Maraganore DM et al (2000) Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. Mov Disord 15:669–677
Sockeel P, Dujardin K, Devos D et al (2006) The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson’s disease. J Neurol Neurosurg Psychiatry 77:579–584
Sokoloff P, Diaz J, Le Foll B et al (2006) The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 5:25–43
Srivanitchapoom P, Pitakpatapee Y, Suengtaworn A (2018) Parkinsonian syndromes: a review. Neurol India 66:S15–S25
Stanwood GD, Artymyshyn RP, Kung MP et al (2000) Quantitative autoradiographic mapping of rat brain dopamine D3 binding with [(125)I]7-OH-PIPAT: evidence for the presence of D3 receptors on dopaminergic and nondopaminergic cell bodies and terminals. J Pharmacol Exp Ther 295:1223–1231
Starkstein SE, Brockman S (2011) Apathy and Parkinson’s disease. Curr Treat Options Neurol 13:267–273
Starkstein SE, Mayberg HS, Preziosi TJ et al (1992) Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 4:134–139
Starkstein SE, Merello M, Jorge R et al (2009) The syndromal validity and nosological position of apathy in Parkinson’s disease. Mov Disord 24:1211–1216
Temel Y, Tan S, Vlamings R et al (2009) Cognitive and limbic effects of deep brain stimulation in preclinical studies. Front Biosci (Landmark Ed) 14:1891–1901
Thobois S, Ardouin C, Lhommee E et al (2010) Non-motor dopamine withdrawal syndrome after surgery for Parkinson’s disease: predictors and underlying mesolimbic denervation. Brain 133:1111–1127
Thobois S, Lhommee E, Klinger H et al (2013) Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain 136:1568–1577
Tong ZY, Kingsbury AE, Foster OJ (2000) Up-regulation of tyrosine hydroxylase mRNA in a sub-population of A10 dopamine neurons in Parkinson’s disease. Brain Res Mol Brain Res 79:45–54
Torack RM, Morris JC (1988) The association of ventral tegmental area histopathology with adult dementia. Arch Neurol 45:497–501
Vachez Y, Carcenac C, Magnard R et al (2020) Subthalamic nucleus stimulation impairs motivation: implication for apathy in Parkinson’s disease. Mov Disord 35:616–628
Volkmann J, Daniels C, Witt K (2010) Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease. Nat Rev Neurol 6:487–498
Voon V, Dalley JW (2011) Parkinson disease: impulsive choice-Parkinson disease and dopaminergic therapy. Nat Rev Neurol 7:541–542
Voon V, Kubu C, Krack P et al (2006) Deep brain stimulation: neuropsychological and neuropsychiatric issues. Mov Disord 21(Suppl 14):S305–S327
Weintraub D, Newberg AB, Cary MS et al (2005) Striatal dopamine transporter imaging correlates with anxiety and depression symptoms in Parkinson’s disease. J Nucl Med 46:227–232
Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483–494
Wise RA, Spindler J, deWit H, Gerberg GJ (1978) Neuroleptic-induced “anhedonia” in rats: pimozide blocks reward quality of food. Science 201:262–264
Yang P, Perlmutter JS, Benzinger TLS et al (2020) Dopamine D3 receptor: a neglected participant in Parkinson disease pathogenesis and treatment? Ageing Res Rev 57:100994
Yin HH, Knowlton BJ (2006) The role of the basal ganglia in habit formation. Nat Rev Neurosci 7:464–476
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Favier, M., Carcenac, C., Savasta, M., Carnicella, S. (2022). Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson’s Disease. In: Boileau, I., Collo, G. (eds) Therapeutic Applications of Dopamine D3 Receptor Function. Current Topics in Behavioral Neurosciences, vol 60. Springer, Cham. https://doi.org/10.1007/7854_2022_316
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