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Title: Compulsive use of dopaminergic drugs in Parkinson's disease : a window into the role of dopamine in addiction and impulse control disorders
Author: Evans, Andrew Howard
ISNI:       0000 0004 2675 1830
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2008
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Parkinson's disease (PD) is a progressive condition that often requires specialist care for a variety of motor and nonmotor symptoms. These symptoms arise from the disease process and also the medications that are used to manage the disease. A small group of patients appear to compulsively use dopaminergic medications well beyond the dose needed to optimally control their motor disability. This destructive behaviour occurs in the face of a mounting number of resulting harmful physical, psychiatric and social sequelae and is encompassed under the term dopamine dysregulation syndrome (DDS). DDS has been linked to punding, and a variety of impulse control disorders (ICDs) such as gambling and hypersexuality. ICDs in particular also occur in relation to dopamine agonist use and in the absence of compulsive dopaminergic drug use. In this thesis, the mechanisms through which dopaminergic treatment of PD may lead to these behavioural changes were explored. It was found that chronic treatment with dopaminergic drugs in PD was able to cross-sensitise to the euphoriant effects of an acute challenge with methylphenidate and L-dopa as well as generally enhance reward responsivity. Regular dopaminergic drug therapy also led to sensitisation to the motor effects of L-dopa. A study to identify drug-induced complex stereotyped motor behaviours (punding) in patients with PD was carried out and found that these behaviours were underrecognised. These behaviours were often socially disabling and the chosen activity tended to reflect the premorbid interests of the patient. They were more common in patients exhibiting other core features of the DDS. This research was driven by the need for more accurate patient characterization. The relative rarity of DDS provides testament to the low addictive liability of dopaminergic drugs used to treat PD but also suggests that it should be possible to identify which individuals about to start dopaminergic therapy are vulnerable to becoming addicted to it. Impulsive sensation seeking personality traits relevant to epidemiological studies of substance dependence and other substance use were found to be highly predictive in the DDS patients as well as an independent association of depressive mood symptoms. Impulsive sensation seeking traits have subsequently been demonstrated to be relevant to individual susceptibility to the emergence of ICDs with treatment with dopamine agonists. The findings propose mechanisms by with patients with the syndrome may be identified and managed early. : DDS patients report and were found to display an aversive drug withdrawal state akin to the withdrawal state with drugs of addiction. The nature of the medication-withdrawal state was characterised in a group of DDS patients after overnight drug withdrawal. In the withdrawal state, DDS patients had more motor Parkinsonism, reduced positive affect, and reported a broader range of affective nonmotor symptoms compared to control patients. With the L-dopa challenge, DDS patients had a greater reduction in the motor UPDRS, number of affective nonmotor symptoms, and a greater increase in reward responsivity and positive affect. In ‘ON’, DDS patients reported increased drug ‘wanting’ but did not ‘feel’ or ‘like’ drug effects more than controls. They had more disabling dyskinesias and showed enhanced reward responsivity. : A novel clinical paradigm of drug dependence was investigated using a two-scan ^{11}C-Raclopride protocol. The results of this study have provided the first human evidence that drug-induced sensitisation of ventral striatal-circuitry mediates compulsive drug ‘wanting’ and is sufficient for the development of substance dependence in humans. These findings are relevant to a broad range of compulsive disorders in general. These observations indicate a pivotal role for dopamine in behavioural addictions, drug-induced stereotypies and drug addiction; and that the brain systems that mediate the transition from drug-use to compulsive drug-taking and craving overlap with systems hat mediate behavioural addictions and the development of drug-induced stereotypies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available