Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders

Dopamine is an essential neurotransmitter for many brain functions, and its dysfunction has been implicated in both neurological and psychiatric disorders. Parkinson's disease is an archetypal disorder of dopamine dysfunction characterised by motor, cognitive, behavioural, and autonomic symptoms. While effective for motor symptoms, dopamine replacement therapy is associated not only with motor side-effects, such as levodopa-induced dyskinesia, but also behavioural side-effects such as impulse control disorders (eg, pathological gambling and shopping, binge eating, and hypersexuality), punding (ie, abnormal repetitive non-goal oriented behaviours), and compulsive medication use. We review clinical features, overlapping molecular mechanisms, and a specific cognitive mechanism of habit learning that might underlie these behaviours. We integrate these mechanisms with the emerging view of the basal ganglia as a distributive system involved in the selection and facilitation of movements, acts, and emotions.

[1]  Paul Greengard,et al.  Critical Involvement of cAMP/DARPP-32 and Extracellular Signal-Regulated Protein Kinase Signaling in l-DOPA-Induced Dyskinesia , 2007, The Journal of Neuroscience.

[2]  W. Schultz,et al.  Neuronal activity in monkey ventral striatum related to the expectation of reward , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  G E Stelmach,et al.  Movement preparation in Parkinson's disease. The use of advance information. , 1986, Brain : a journal of neurology.

[4]  K. Fuxe,et al.  Increase in A2A receptors in the nucleus accumbens after extended cocaine self-administration and its disappearance after cocaine withdrawal , 2007, Brain Research.

[5]  R. Boakes,et al.  Motivational control after extended instrumental training , 1995 .

[6]  Regina Katzenschlager,et al.  Punding in Parkinson's disease: Its relation to the dopamine dysregulation syndrome , 2004, Movement disorders : official journal of the Movement Disorder Society.

[7]  V. Voon,et al.  Medication-related impulse control and repetitive behaviors in Parkinson disease. , 2007, Archives of neurology.

[8]  A J Lees,et al.  Relationship between impulsive sensation seeking traits, smoking, alcohol and caffeine intake, and Parkinson’s disease , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[9]  A. Sorkin,et al.  Rapid regulation of the dopamine transporter: role in stimulant addiction? , 2004, Neuropharmacology.

[10]  Erwan Bezard,et al.  Pathophysiology of levodopa-induced dyskinesia: Potential for new therapies , 2001, Nature Reviews Neuroscience.

[11]  J. González-Mora,et al.  Heterogeneous Dopamine Neurochemistry in the Striatum: The Fountain-Drain Matrix , 2006, Journal of Pharmacology and Experimental Therapeutics.

[12]  G. Halliday,et al.  The progression of pathology in longitudinally followed patients with Parkinson’s disease , 2008, Acta Neuropathologica.

[13]  J. Marinus,et al.  Psychotic and compulsive symptoms in Parkinson's disease , 2009, Movement disorders : official journal of the Movement Disorder Society.

[14]  P. Sokoloff,et al.  Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  E. Bézard,et al.  Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms , 2009, The Lancet Neurology.

[16]  B. Sahakian,et al.  Predictors of punding in Parkinson's disease: Results from a questionnaire survey , 2007, Movement disorders : official journal of the Movement Disorder Society.

[17]  P. Jenner,et al.  Alterations in preproenkephalin and adenosine‐2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with l‐DOPA , 2000, The European journal of neuroscience.

[18]  J. Régis,et al.  Addiction in Parkinson's disease: Impact of subthalamic nucleus deep brain stimulation , 2005, Movement disorders : official journal of the Movement Disorder Society.

[19]  P. Apicella,et al.  Reward-related neuronal activity in the subthalamic nucleus of the monkey , 2005, Neuroreport.

[20]  K. Berridge,et al.  The neural basis of drug craving: An incentive-sensitization theory of addiction , 1993, Brain Research Reviews.

[21]  J. Girault,et al.  Persistent Increase in Olfactory Type G-Protein α Subunit Levels May Underlie D1 Receptor Functional Hypersensitivity in Parkinson Disease , 2004, The Journal of Neuroscience.

[22]  N. A. Buchwald,et al.  Effects of caudate nuclei or frontal cortical ablations in kittens: Motor activity and visual discrimination performance in neonatal and juvenile kittens , 1978, Experimental Neurology.

[23]  R. Kessler,et al.  The Prevalence and Correlates of Eating Disorders in the National Comorbidity Survey Replication , 2007, Biological Psychiatry.

[24]  G. Di Chiara,et al.  Agonist-induced homologous and heterologous sensitization to D-1- and D-2-dependent contraversive turning. , 1987, European journal of pharmacology.

[25]  Nikolaus R. McFarland,et al.  Striatonigrostriatal Pathways in Primates Form an Ascending Spiral from the Shell to the Dorsolateral Striatum , 2000, The Journal of Neuroscience.

[26]  E. Vaadia,et al.  Coincident but Distinct Messages of Midbrain Dopamine and Striatal Tonically Active Neurons , 2004, Neuron.

[27]  Y. Shaham,et al.  Role of ERK in cocaine addiction , 2006, Trends in Neurosciences.

[28]  O. Rascol,et al.  Development of dyskinesias in a 5‐year trial of ropinirole and L‐dopa , 2006, Movement disorders : official journal of the Movement Disorder Society.

[29]  C. Marsden,et al.  Disturbance of sequential movements in patients with Parkinson's disease. , 1987, Brain : a journal of neurology.

[30]  Paul Greengard,et al.  Cell type–specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs , 2008, Nature Neuroscience.

[31]  J. Vander Bilt,et al.  Estimating the prevalence of disordered gambling behavior in the United States and Canada: a research synthesis. , 1999, American journal of public health.

[32]  Y. Agid,et al.  Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation , 2006, Movement disorders : official journal of the Movement Disorder Society.

[33]  E. Bézard,et al.  Pharmacological Analysis Demonstrates Dramatic Alteration of D1 Dopamine Receptor Neuronal Distribution in the Rat Analog of l-DOPA-Induced Dyskinesia , 2009, The Journal of Neuroscience.

[34]  B Bioulac,et al.  Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey. , 2001, Brain : a journal of neurology.

[35]  A. Doupe,et al.  Interruption of a basal ganglia–forebrain circuit prevents plasticity of learned vocalizations , 2000, Nature.

[36]  S. Cragg,et al.  Dopamine spillover after quantal release: Rethinking dopamine transmission in the nigrostriatal pathway , 2008, Brain Research Reviews.

[37]  A. Faure,et al.  Lesion to the Nigrostriatal Dopamine System Disrupts Stimulus-Response Habit Formation , 2005, The Journal of Neuroscience.

[38]  A. Lang,et al.  Prospective prevalence of pathologic gambling and medication association in Parkinson disease , 2006, Neurology.

[39]  Thomas Boraud,et al.  Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function , 2003, Nature Medicine.

[40]  Qin Li,et al.  The 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitor Lovastatin Reduces Severity of l-DOPA-Induced Abnormal Involuntary Movements in Experimental Parkinson's Disease , 2008, The Journal of Neuroscience.

[41]  E. Bézard,et al.  Molecular mechanisms of l-DOPA-induced dyskinesia. , 2011, International review of neurobiology.

[42]  P. Emson,et al.  Altered vesicular dopamine storage in Parkinson's disease: a premature demise , 2008, Trends in Neurosciences.

[43]  O. Hornykiewicz,et al.  Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson's disease , 2003, Neurobiology of Disease.

[44]  B. Everitt,et al.  Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum , 2008, Neuron.

[45]  J A Obeso,et al.  Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson's disease. , 2006, Brain : a journal of neurology.

[46]  S. Wong,et al.  Internet gambling and other pathological gambling in Parkinson's disease: A case series , 2007, Movement disorders : official journal of the Movement Disorder Society.

[47]  S Fahn,et al.  The spectrum of levodopa-induced dyskinesias. , 2000, Annals of neurology.

[48]  J. Dostrovsky,et al.  Neuronal recordings in Parkinson's disease patients with dyskinesias induced by apomorphine. , 2000, Annals of neurology.

[49]  T. Robbins,et al.  Review Personality, Addiction, Dopamine: Insights from Parkinson's Disease Table 1. Possible Site of Striatal Dopamine Dysfunction Causing Different Motor and Cognitive Symptoms in Parkinson's Disease , 2022 .

[50]  Luigi F. Agnati,et al.  The emergence of the volume transmission concept 1 Published on the World Wide Web on 12 January 1998. 1 , 1998, Brain Research Reviews.

[51]  K. Campbell,et al.  A neural correlate of response bias in monkey caudate nucleus , 2022 .

[52]  C. Konradi,et al.  Spatiotemporal Pattern of Striatal ERK1/2 Phosphorylation in a Rat Model of L-DOPA–Induced Dyskinesia and the Role of Dopamine D1 Receptors , 2007, Biological Psychiatry.

[53]  R. J. McDonald,et al.  A triple dissociation of memory systems: hippocampus, amygdala, and dorsal striatum. , 1993, Behavioral neuroscience.

[54]  M. Potenza Non-substance and substance addictions. , 2009, Addiction.

[55]  J. Wickens,et al.  A cellular mechanism of reward-related learning , 2001, Nature.

[56]  J M Smith,et al.  Compulsive buying: a report of 20 cases. , 1994, The Journal of clinical psychiatry.

[57]  B. Balleine,et al.  Inactivation of dorsolateral striatum enhances sensitivity to changes in the action–outcome contingency in instrumental conditioning , 2006, Behavioural Brain Research.

[58]  M. West,et al.  Changes in activity of the striatum during formation of a motor habit , 2007, The European journal of neuroscience.

[59]  M. Kimura Behaviorally contingent property of movement-related activity of the primate putamen. , 1990, Journal of neurophysiology.

[60]  P. Kuhl,et al.  Birdsong and human speech: common themes and mechanisms. , 1999, Annual review of neuroscience.

[61]  W. Ondo,et al.  Predictors of impulsivity and reward seeking behavior with dopamine agonists. , 2008, Parkinsonism & related disorders.

[62]  B. Everitt,et al.  Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex , 2002, Neuroscience & Biobehavioral Reviews.

[63]  T. Robbins,et al.  Probabilistic learning and reversal deficits in patients with Parkinson’s disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication , 2000, Neuropsychologia.

[64]  F. Jiménez-Jiménez,et al.  Pathologic gambling in Parkinson's disease: A behavioral manifestation of pharmacologic treatment? , 2000, Movement disorders : official journal of the Movement Disorder Society.

[65]  J. Hollerman,et al.  Influence of reward expectation on behavior-related neuronal activity in primate striatum. , 1998, Journal of neurophysiology.

[66]  P. Jenner,et al.  Plasma levels of rotigotine and the reversal of motor deficits in MPTP-treated primates , 2007, Behavioural pharmacology.

[67]  A. Graybiel,et al.  The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. , 1999, Brain : a journal of neurology.

[68]  Gilberto Fisone,et al.  Increased D1 dopamine receptor signaling in levodopa‐induced dyskinesia , 2005, Annals of neurology.

[69]  J. Kassubek,et al.  Dopamine Agonists and their risk to induce psychotic episodes in Parkinson's disease: a case-control study , 2009, BMC neurology.

[70]  Erwan Bezard,et al.  Involvement of Sensorimotor, Limbic, and Associative Basal Ganglia Domains in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia , 2005, The Journal of Neuroscience.

[71]  A. Graybiel,et al.  The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. , 1999, Brain : a journal of neurology.

[72]  R. Katzenschlager,et al.  Punding and dyskinesias , 2006, Movement disorders : official journal of the Movement Disorder Society.

[73]  A. Lang,et al.  Punding prevalence in Parkinson's disease , 2007, Movement Disorders.

[74]  G. Rylander Psychoses and the punding and choreiform syndromes in addiction to central stimulant drugs. , 1972, Psychiatria, neurologia, neurochirurgia.

[75]  J. Obeso,et al.  Clinical Features, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesias in Parkinson's Disease , 2012, Parkinson's disease.

[76]  Paul Greengard,et al.  Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesia , 2003, Nature Neuroscience.

[77]  H. E. Rosvold,et al.  Behavioral effects of selective ablation of the caudate nucleus. , 1967, Journal of comparative and physiological psychology.

[78]  N. Pavón,et al.  ERK Phosphorylation and FosB Expression Are Associated with L-DOPA-Induced Dyskinesia in Hemiparkinsonian Mice , 2006, Biological Psychiatry.

[79]  Yen F. Tai,et al.  Compulsive drug use linked to sensitized ventral striatal dopamine transmission , 2006, Annals of neurology.

[80]  J. Doyon Motor sequence learning and movement disorders , 2008, Current opinion in neurology.

[81]  R. J. McDonald,et al.  Multiple Parallel Memory Systems in the Brain of the Rat , 2002, Neurobiology of Learning and Memory.

[82]  J A Obeso,et al.  Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems with the current model. , 2000, Annals of neurology.

[83]  D. Grosset,et al.  Problematic gambling on dopamine agonists: Not such a rarity , 2006, Movement disorders : official journal of the Movement Disorder Society.

[84]  Ronald J. Faber,et al.  Estimated prevalence of compulsive buying behavior in the United States. , 2006, The American journal of psychiatry.

[85]  C. Colosimo,et al.  Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson's disease , 2005, Movement disorders : official journal of the Movement Disorder Society.

[86]  S. Young,et al.  5-hydroxydopamine-labeled dopaminergic axns: Three-dimensional reconstructions of axons, synapses and postsynaptic targets in rat neostriatum , 1994, Neuroscience.

[87]  B. Balleine,et al.  Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning , 2004, The European journal of neuroscience.

[88]  K. Fuxe,et al.  Localization of monoamines in the lower brain stem , 1964, Experientia.

[89]  V. Voon,et al.  Medication-related impulse control and repetitive behaviors in Parkinson's disease , 2007, Current opinion in neurology.

[90]  Vesna Sossi,et al.  Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias. , 2004, Brain : a journal of neurology.

[91]  G. Brighetti,et al.  Prevalence of pathological gambling in patients with Parkinson's disease , 2006, Movement disorders : official journal of the Movement Disorder Society.

[92]  G. Fénelon Psychosis in Parkinson's Disease: Phenomenology, Frequency, Risk Factors, and Current Understanding of Pathophysiologic Mechanisms , 2008, CNS Spectrums.

[93]  A. Lawrence,et al.  Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson disease , 2005, Neurology.

[94]  A. Graybiel,et al.  Subdivisions of the dopamine-containing A8-A9-A10 complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal matrix , 1987, Neuroscience.

[95]  J. Obeso,et al.  Levodopa‐induced dyskinesias in Parkinson's disease: Clinical and pharmacological classification , 1992, Movement disorders : official journal of the Movement Disorder Society.

[96]  Christopher D. Adams,et al.  The Effect of the Instrumental Training Contingency on Susceptibility to Reinforcer Devaluation , 1983 .

[97]  P. Moberg,et al.  Association of dopamine agonist use with impulse control disorders in Parkinson disease. , 2006, Archives of neurology.

[98]  E. Bézard,et al.  Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracelullar striatal dopamine , 2006, Neurobiology of Disease.

[99]  C. Goetz,et al.  Levodopa‐induced dyskinesias , 2007, Movement disorders : official journal of the Movement Disorder Society.

[100]  Michael J. Frank,et al.  Hold Your Horses: Impulsivity, Deep Brain Stimulation, and Medication in Parkinsonism , 2007, Science.

[101]  J. Wickens,et al.  Dopamine reverses the depression of rat corticostriatal synapses which normally follows high-frequency stimulation of cortex In vitro , 1996, Neuroscience.

[102]  J. Villablanca,et al.  Effects of caudate nuclei or frontal cortex ablations in cats. IV. Bar pressing, maze learning, and performance , 1976, Experimental Neurology.

[103]  M. Kuhar,et al.  The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[104]  R. Beninger,et al.  Impaired Incentive Learning in Treated Parkinson’s Disease , 1996, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[105]  R. Brambilla Targeting Ras/ERK signaling in the striatum: will it help? , 2003, Molecular Psychiatry.

[106]  T. Robbins,et al.  The cognitive ability of an incident cohort of Parkinson's patients in the UK. The CamPaIGN study. , 2004, Brain : a journal of neurology.

[107]  B. Knowlton,et al.  Learning and memory functions of the Basal Ganglia. , 2002, Annual review of neuroscience.

[108]  M. Amalric,et al.  The subthalamic nucleus exerts opposite control on cocaine and 'natural' rewards , 2005, Nature Neuroscience.

[109]  R. Cantello Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies , 2000, Journal of neurology, neurosurgery, and psychiatry.

[110]  A. Kelley Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning , 2004, Neuroscience & Biobehavioral Reviews.

[111]  A. Lang,et al.  Prevalence of repetitive and reward-seeking behaviors in Parkinson disease , 2006, Neurology.

[112]  L. Metman,et al.  Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease , 1998, Neurology.