Parkinson’s disease: A promise for the future

Parkinson’s disease is a neurological condition affecting approximately 40,000 Australians. The disease is caused by the death of nerve cells in the brain responsible for producing dopamine; the chemical messenger that allows different parts of the brain to coordinate body movement. The initial symptom of Parkinson’s disease is usually a tremor, but symptoms can include rigidity, poor balance, and limited movement. Non-motor symptoms include changes in mood and cognition, hallucinations or delusions and sleep problems. As the disease progresses it becomes increasingly difficult for the individual to live independently. Parkinson’s disease is chronic and degenerative – that is, there is no known cure.

The initial observation of symptoms that would later become known as Parkinson’s disease occurred in 1817. It wasn’t until the 1950s, when a succession of major discoveries revealed dopamine loss was a factor in the onset of Parkinson’s disease and dopamine itself was implicated in the control of movement, that the first truly effective treatment for Parkinson’s disease was discovered. Levodopa (L-DOPA) is an amino acid that the body converts into dopamine but that, unlike dopamine, can be taken orally and is able to cross the blood – brain barrier. Given that the loss of cells able to produce dopamine is implicated in the pathogenesis of Parkinson’s disease, L-DOPA was the subject of its first, successful clinical trial in 1961.

Researchers experimented with different dosages of L-DOPA administering it in conjunction with other drugs to enhance its efficacy. L-DOPA, administered with drugs that control negative gastro-intestinal side effects, is still considered the gold-standard in treatment. However, it became clear that the effects of the drug ‘wear off’ before the next dose can be taken. So, research began into dopamine agonists. Dopamine agonists bind to dopamine receptors in the brain, essentially tricking the brain into thinking there is adequate dopamine around. The result is a reduction in Parkinson’s related motor symptoms. L-DOPA and dopamine agonists share some common side effects, including nausea and vomiting, and hallucinations. However, dopamine agonists come with the risk of a few unique side effects, like sleepiness and the appearance of impulsive or compulsive behaviour, for example pathological gambling.

Sorry, what was that last bit? Yes, well, routine treatment of Parkinson’s disease with dopamine agonists began in the early 1970s. Around 30 years later findings started to emerge indicating that a number of patients affected by Parkinson’s disease and treated with dopamine agonists developed pathological gambling behaviours, far beyond that which would be expected based on the prevalence of the disorder in the general population. Dopamine is the master manipulator behind not only motor movement, but also reward and motivation. That is, dopamine is released to motivate you to achieve a goal and helps to reinforce the thrill when that achievement is unlocked. Researchers suppose that treatment with dopamine agonists may increase an individual’s motivation, as well as their sensitivity to reward. Why gambling? That is less clear. However, a pre-existing tendency towards low impulse control and high novelty-seeking can make someone more vulnerable, as can a personal or family history of addiction. There’s some evidence that younger patients are more likely to develop these side effects, but it has also been argued that this effect is primarily due to more young patients being prescribed dopamine agonists than older patients.

Around 17 per cent of people with Parkinson’s disease treated with dopamine agonists experience impulsive and compulsive behaviour as a side effect, most often gambling but also compulsive sexual behaviour, compulsive spending and binge-eating. L-DOPA doesn’t get off scot-free here, with research showing that seven per cent of people taking this kind of medication may experience similar side effects.

It is a uniquely cruel twist of the knife that people affected by this devastating illness may have to also shoulder the burden of impulsive or compulsive behaviour. Research is, as always, ongoing, with recent findings from researchers at the University of Queensland suggesting there may even be hope that the loss of brain cells in those affected by Parkinson’s disease could be stopped by administering a small molecule, MMC950. It is anticipated that human clinical trials will begin in 2020. Here’s hoping.

Dr Jessica L Paterson, Senior Research Fellow, CQUniversity, Appleton Institute

@drjesspaterson

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