Journal of Clinical Neuroscience 18 (2011) 191–192

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Journal of Clinical Neuroscience

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Dopamine agonist-induced substance addiction: The next piece of the puzzle

Andrew Evans *

Department of Neurology, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia

a r t i c l e i n f o a b s t r a c t

Article history:Received 17 February 2010Accepted 12 April 2010

Keywords:Dopamine agonistImpulse control disorderRewardSubstance dependence

0967-5868/$ - see front matter � 2010 Elsevier Ltd. Adoi:10.1016/j.jocn.2010.04.024

* Tel.: +61 3 9342 8448; fax: +61 3 9342 8427.E-mail address: Andrew.Evans@mh.org.au

Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminer-gic drugs with the avoidance of motor response complications. Dopamine agonists have an establishedrole in delaying the emergence of motor response complications or reducing motor ‘‘off” periods. Therecent recognition of a range of ‘‘behavioural addictions” that are linked to dopamine agonist use hashighlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamineagonists have now even been linked occasionally to new substance addictions. The challenge now for theParkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effectswith avoiding the harm from behavioural compulsions.

� 2010 Elsevier Ltd. All rights reserved.

Parkinson’s disease (PD) therapies mainly exploit the notion systematic prevalence estimates for any common ICD are around

that dopaminergic drugs can replenish striatal dopamine andthereby reduce bradykinesia and rigidity. Treatment strategieshave traditionally tried to balance the antiparkinson effects ofthe medications with the avoidance of motor response complica-tions that emerge as the nigrostriatal dopamine system degener-ates and drug requirements increase. Adding dopamine agoniststo levodopa treatment has an important role in reducing fluctuat-ing motor responses.1 In de novo patients, dopamine agonists candelay the need for treatment with levodopa and consequentlydefer the onset of complications such as dyskinesia.2 Dopamineagonists may have additional beneficial effects on mood andmotivational symptoms in patients with PD.3

These treatment strategies have coincided with the recognitionof a range of ‘‘behavioural addictions” that are linked by theirrepetitive, reward or incentive-based natures. These impulsiveand compulsive behaviours include a range of impulse control dis-orders (ICD), punding (complex repetitive stereotypies), hoardingbehaviours, and occasionally even compulsive use of the dopami-nergic drug therapies themselves (dopamine dysregulation syn-drome [DDS]).4–7 ICD are characterised by an intensified focus onrewarding or pleasurable behaviours that are performed repeti-tively, excessively, and/or compulsively and to an extent that inter-feres in areas of life functioning. Common ICD include problem orpathological gambling, compulsive buying, compulsive eating andhypersexuality, and have been found to have similar prevalences.6

Rarer behavioural addictions include compulsive reckless generos-ity and compulsive reckless driving.8

Impulsive and compulsive behaviours are an important poten-tial source of additional morbidity in PD. In North America, recent

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14%. In cross-sectional studies of patients with PD, dopamine ago-nist use and total dopamine agonist dose in particular, are linked toICD. Levodopa monotherapy is much less frequently associatedwith ICD.6 The prevalence of punding is less – estimated between1.4% and 14% and DDS has been estimated to affect up to 4% of ter-tiary outpatients.

Drug-induced changes in cognition and personality may under-pin the emergence of impulsive and compulsive behaviours intreated patients with PD. Initiation of regular treatment with dopa-minergic therapies in de novo patients has been linked to variouschanges in reward processing; such as enhanced psychomotoreffects from an acute challenge with different dopaminergicdrugs.9 Initiating regular treatment with a dopamine agonist inyoung patients with PD leads to increases in novelty seeking,enhanced reward processing, and decreased punishment process-ing. ICD have been therefore been conceptualised as resulting fromlong-term exposure to dopaminergic agonists leading to differen-tial effects on brain reward processing in vulnerableindividuals.10,11

The neurobiological systems mediating impulsive and compul-sive behaviours in PD at least overlap. There are significant phe-nomenological commonalities between the behaviours. Overlapsin vulnerability factors between DDS, punding and ICD includeyounger age PD onset, risk-prone personality, total daily dopami-nergic drug dose and depression.12,13 Patients with PD who usetheir drugs compulsively show heightened endogenous dopamineresponses in the nucleus accumbens to an oral dose of levodopa.14

The nucleus accumbens also appears to be hyper-responsive togambling reward in patients with PD who have agonist-inducedpathological gambling.15

The report of Bienfait et al.16 highlights the link between dopa-mine agonist treatment and the potential for early development of

192 A. Evans / Journal of Clinical Neuroscience 18 (2011) 191–192

compulsive behaviours – in particular, emergence of a new sub-stance addiction. It should be noted that the daily dose of pramip-exole leading to the compulsive behavioural disorders in Bienfiat’spatient (6 mg/day) was higher than the maximum recommendeddaily dose (4.5 mg/day). The few cases reported where dopamineagonist treatment has induced a new substance addiction6 providean important additional link between the role of exogenous dopa-minergic stimulation and the development of addiction disordersin general. The case reported by Bienfait et al. also demonstratesthat individuals with ICD may experience a global sensitisationof reward-focused behaviours – as multiple forms of compulsivebehaviour often occur in the same individual. Individuals whoexperience an ICD in the course of treatment with a dopamine ago-nist also tend to have an enduring tendency to relapse – presum-ably through drug-induced neuroplastic changes in brain rewardfunction, disease-induced deterioration in cognitive functionsand/or enduring individual psychosocial factors.

Observations like these support the notion that that as far as thebrain is concerned – a reward is a reward – regardless of whether itcomes from a chemical or an experience.17 And when dopaminer-gic drugs are given to a brain, there is the risk that the drugs canhijack brain reward systems and lead to the brain getting trappedin a compulsion. The challenge now for the Parkinsonologist is tobalance the net benefits of using dopamine agonists for their motoreffects with minimising the harm from behavioural compulsions.

References

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11. Lawrence AD, Evans AH, Lees AJ. Compulsive use of dopamine replacementtherapy in Parkinson’s disease: reward systems gone awry? Lancet Neurol2003;2:595–604.

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14. Evans AH, Pavese N, Lawrence AD, et al. Compulsive drug use linked tosensitized ventral striatal dopamine transmission. Ann Neurol 2006;59:852–8.

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