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