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Compulsive use of dopaminergic drugs in Parkinson's disease.

Evans, A.H.; (2008) Compulsive use of dopaminergic drugs in Parkinson's disease. Doctoral thesis , University of London. Green open access

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A small group of patients with Parkinson's disease (PD) compulsively use dopaminergic medications despite the frequent emergence of harmful physical, psychiatric and social effects. This behavioural syndrome has been termed the dopamine dysregulation syndrome (DDS) and although closely related, should be distinguished from impulse control disorders. The phenomenology, risk factors and neurobiology of DDS have been explored in a series of observational, neuropsychological and pharmacological clinical studies. Dopaminergic drug-responsive complex repetitive stereotypical behaviours (punding) were identified and characterised in PD outpatients selected on the basis of their dopaminergic drug intake. In animal models of Parkinson's disease, stereotypies are known to index the neuroadaptive changes of sensitisation. Punding was found to be associated with DDS, dyskinesia severity and harmful neuropsychiatric disturbances raising the possibility that the biological mechanisms underlying drug-reward and these behaviours may overlap. Psychostimulant drugs have powerful effects on dopamine release and re-uptake in the presynaptic dopamine system and are capable of inducing neuroplastic changes in the basal ganglia particularly after their intermittent administration. Psychostimulant drugs have dopaminergic effects but have only been demonstrated to have weak anti-Parkinsonian effects. The acute effects of L-dopa and methylphenidate were examined (which has effects similar to psychostimulant drugs) in 15 untreated PD patients, before and again after a mean 18 months of sustained dopaminergic drug therapy. After sustained dopaminergic therapy, the motor effects of L-dopa and the euphoriant effects of methylphenidate were augmented. This provided clinical support in humans for the first time that sustained dopaminergic drug therapy may result in psychomotor sensitisation. In an effort to facilitate early identification of DDS and for planning prompt therapeutic interventions personality traits were examined in PD patients with DDS and compared to those without DDS and healthy controls. DDS patients were found to differ from control PD patients and age-matched healthy controls in personality dimensions linked with substance dependence i.e. high impulsive sensation seeking traits, low harm avoidance, reward dependence, self-directedness and cooperativeness. Impulsive sensation seeking traits in particular, in addition to premorbid addictive behaviour were also found to predict the emergence of DDS suggesting a common neurobiological vulnerability. DDS patients complain of an aversive drug withdrawal state akin to the withdrawal state seen in other forms of addiction. Many patients attribute avoidance of aversive "ofTs" as the reason behind their compulsive drive to self-medicate. This aversive "off'-state was examined in 20 DDS patients and PD controls and found to be associated with behaviours that may lead to sensitisation of brain reward systems. Most authorities believe that compulsive drug-taking and associated behavioural disorders are mediated through the mesolimbic dopaminergic projections and the nucleus accumbens. DDS was investigated using a two-scan nC-Raclopride protocol. Drug-induced sensitisation of ventral striatal- circuitry appeared to mediate compulsive drug "wanting" - providing the first evidence of such in humans. Greater understanding of compulsive dopaminergic drug use in PD should not only inform the management of PD but may provide insight into the mechanisms underlying impulse control disorders.

Type: Thesis (Doctoral)
Title: Compulsive use of dopaminergic drugs in Parkinson's disease.
Identifier: PQ ETD:591565
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1444263
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