Elsevier

The Lancet Neurology

Volume 8, Issue 12, December 2009, Pages 1140-1149
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(09)70287-XGet rights and content

Summary

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.

Introduction

Dopamine neuromodulation is intrinsic to processes of movement and motor learning, cognition, reward processing, food intake, nociception, and endocrine and autonomic regulation. Dopaminergic dysfunction is implicated in neurological and neuropsychiatric disorders such as Parkinson's disease (PD), schizophrenia, and drug addiction. PD is associated with both dopamine-related motor and behavioural side-effects and provides a useful model to understand the similarities and differences underlying the effects of dopamine on motor and behavioural disorders.

PD is characterised by the loss of dopaminergic nigrostriatal A9 neurons (and, to a lesser extent, retrorubral A8 and mesolimbic A10 neurons); with disease progression, non-dopaminergic nuclei, such as the locus coeruleus, the nucleus basalis of Meynert, and the dorsal raphe, are affected, and Lewy body pathology becomes widespread.1 The dopamine replacement therapies, which include the dopamine precursor levodopa and dopamine agonists, are very effective in treating motor symptoms, but can cause substantial motor and behavioural adverse events. These side-effects include motor fluctuations and levodopa-induced dyskinesia (LID),2 and non-motor symptoms such as mood and anxiety fluctuations, psychosis, and impulse control disorders (ICDs). LIDs are defined as involuntary, purposeless, irregular but sometimes repetitive movements, which are mainly choreic, and generally coincide with the peak anti-parkinsonian effect of levodopa.3 LIDs affect at least 90% of patients with PD after 10 years of levodopa treatment4 and are a major cause of disability. ICDs (ie, pathological gambling, compulsive shopping, hypersexuality, and binge eating), punding (ie, abnormal repetitive non-goal oriented behaviours) or hobbyism, and compulsive medication use are associated with dopaminergic therapy and are increasingly recognised in PD.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 Overall, the ICDs in the general population have similarities to disorders of substance addiction, hence ICDs have been viewed as behavioural addictions.16 The pathology of PD and the mechanisms underlying LIDs, a dopamine-associated motor side-effect, are better defined than are the mechanisms underlying ICDs, for which much less is understood. In this Review, we provide insights into potential mechanisms underlying ICDs and discuss potential similarities and differences between LIDs and ICDs.

Section snippets

Levodopa-induced dyskinesias

The clinical features and major presentation types of LIDs have been described and discussed extensively in the literature (panel 1).17, 18 LIDs commonly occur in patients with motor fluctuations and are related to levodopa intake. The main risk factors associated with LIDs are disease severity, disease duration, daily dose of levodopa, and age at onset (ie, 50% of patients aged 45 years or less develop LIDs within the first 2 years of treatment).3, 4 Monotherapy with dopamine agonists such as

Dopaminergic mechanisms and abnormal behaviours

The main dopaminergic projections are part of the retrorubral field (A8), nigrostriatal (A9), mesocorticolimbic (A10), diencephalospinal (A11), and hypothalamoinfundibular (A12, A13, A14) systems.37 Although dopamine cell group projections are topographically organised, the segregation is not absolute; the motor dorsal striatum and limbic ventral striatum receive innervation from all three mesencephalic dopamine cell groups.38 Furthermore, the midbrain dopaminergic neurons are reciprocally

Conclusions: are behavioural and motor disorders in PD part of the same continuum?

The basal ganglia forms a complex network that is involved in the selection and facilitation or the inhibition of movements, acts, and emotions.111 This integrated view leads to the natural speculation that the pathological consequences of dopamine dysfunction might involve unwanted movements, acts, and emotions. We suggest that the involuntary movements of LIDs and behavioural disorders of ICDs, punding, and compulsive medication use are part of a continuum and are the motor, cognitive, and

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the terms “dopamine”, “parkinson”, “dyskinesia”, “compulsive”, “behaviour”, and “addiction” from 1966 until March, 2009. Articles were also identified through searches of the authors' own files. Only papers in English were reviewed.

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