Why do some Parkinson’s treatments affect decision making?

Parkinson’s disease (PD), also known simply as Parkinson’s, is a nervous system disorder that affects millions of people worldwide. Damage to nerve cells associated with Parkinson’s disease can cause tremors, slowed movement, balance problems, and many other symptoms that gradually worsen over time.

Although there is no cure, there are medications that can treat the symptoms of Parkinson’s disease. However, some of these medications have previously unexplained side effects, including impaired decision-making that leads to potentially dangerous behaviors such as pathological gambling, binge eating, and compulsive shopping.

However, in a study published online on August 14, 2024 in the International Journal of Molecular SciencesResearchers at Fujita Health University in Japan, led by Assistant Professor Hisayoshi Kubota of the Division of Behavioral Neuropharmacology at the International Center for Brain Science (ICBS) at Fujita Health University, investigated the mechanism by which a drug called pramipexole or PPX impairs decision-making in mice with Parkinson’s disease.

The research was co-authored by Professor Taku Nagai of the Division of Behavioral Neuropharmacology at the International Center for Brain Science (ICBS) and Professor Hirohisa Watanabe of the Department of Neurology, Faculty of Medicine, both at Fujita Health University.

To take a closer look at the results of this study, we first need to understand how PPX works to relieve the symptoms of Parkinson’s disease. Parkinson’s disease primarily results from a loss of nerve cells, or neurons, that produce a compound called dopamine.

Some neurons rely on dopamine for their normal function. They have structures called “dopamine receptors” that can be thought of as locks that can then be activated using dopamine as a “key.” Drugs like PPX can mimic the function of dopamine and bind to these receptors instead, especially in PD patients who lack dopamine-producing neurons.

To study the effects of PPX on Parkinson’s disease, the researchers injected mice into their brains with a toxin called 6-hydroxydopamine (or 6-OHDA). 6-OHDA damages neurons in a way very similar to that seen in the brains of Parkinson’s patients. The mice were treated with PPX and then given a touchscreen “gaming task” to test their decision-making abilities.

Interestingly, these mice chose the high-risk/high-reward option much more often: they opted for a disadvantageous outcome where they received a large reward (a strawberry milkshake), which also came with an increased risk of significant punishment through exposure to flashing lights.

But what part of the brain is responsible for this behavior? Studying the brains of mice treated with PPX revealed that a region located deep in the brain, called the external globus pallidus (GPe), was hyperactivated, that is, it had a much higher level of neuronal activity.

The researchers then chemically inhibited the GPe neurons, which effectively reduced the disadvantageous risk-taking activity in the mice. This proved that GPe hyperactivation was indeed responsible for poor decision-making in the PPX-treated mice.

This study has implications for the treatment of patients with Parkinson’s disease. “Our findings could lead to the development of new drugs or interventions that specifically target the external globus pallidus,” says Dr. Kubota. “This could help prevent or reduce decision-making impairment in patients with Parkinson’s disease.”

In addition to helping healthcare professionals develop better treatments for Parkinson’s disease, these findings may also help improve awareness among affected patients, their families, and the general public.

Dr. Kubota explains: “Studying how Parkinson’s disease medications affect decision-making will help the public better understand the complexity of the disease and its treatment. This will benefit patients, their families and caregivers, and motivate them to consider early care and prevention strategies.”

These results shed new light on the complex brain processes that facilitate our everyday decision-making and promise to improve the quality of life of patients with Parkinson’s disease.