Summary: Pramipexole, a Parkinson’s disease (PD) drug, impairs decision-making by hyperactivating the brain’s external globus pallidus (GPe) region. This research uncovers how the medication, while effective for PD symptoms, can lead to risky behaviors like gambling.
The findings offer hope for developing treatments that reduce these side effects by targeting the GPe. Understanding this mechanism may lead to improved quality of life for Parkinson’s patients.
Key Facts:
- Pramipexole hyperactivates the GPe, causing poor decision-making in PD.
- Study shows mice chose risky outcomes more often after PPX treatment.
- Targeting the GPe may reduce these cognitive side effects in PD patients.
Source: Fujita Health University
Parkinson’s disease (PD), also known simply as Parkinson’s, is a disorder of the nervous system that affects millions of people worldwide. The nerve cell damage associated with Parkinson’s can cause tremors, slowed movements, problems with balance, and many other symptoms that worsen gradually over time.
Although there is no cure, there are medications available that can treat PD symptoms. Some of these medications, however, have previously unexplained side effects – including impaired decision-making that leads to potentially harmful behaviors such as pathological gambling, binge eating and compulsive shopping.
Now, in a study published online on 14 August 2024 in the International Journal of Molecular Sciences, researchers at Fujita Health University in Japan, led by Assistant Professor Hisayoshi Kubota from the Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, have investigated the mechanism by which a drug called pramipexole or PPX impairs the decision-making process in mice with Parkinson’s disease.
The research was co-authored by Professor Taku Nagai from the Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), and Professor Hirohisa Watanabe from the Department of Neurology, School of Medicine, both at Fujita Health University.
To take a closer look at the findings of this study, we first need to understand how PPX works to alleviate PD symptoms. PD mainly results from a loss of nerve cells or neurons that produce a compound called dopamine.
Some neurons are dependent on dopamine for their regular functioning – they have structures called ‘dopamine receptors’ which can be thought of as locks which can then be activated using dopamine as the ‘key’.
Drugs like PPX can imitate the function of dopamine and bind to these receptors instead, especially in patients with PD who lack dopamine-producing neurons.
To study the effects of PPX on PD, the researchers injected the brains of mice with a toxin called 6-hydroxydopamine (or 6-OHDA). 6-OHDA damages neurons in a very similar manner to that observed in the brains of patients with PD.
The mice were treated with PPX and then subjected to a touchscreen-based ‘gambling task’ to test their decision-making skills. Interestingly, these mice picked the high-risk/high-reward option much more often – they opted for a disadvantageous outcome where they received a large reward (of strawberry milkshake), which also comes with an increased risk of a large punishment by exposure to flashing lights.
But which part of the brain is responsible for this behavior? Investigating the brains of mice treated with PPX revealed that a region deep inside the brain called the external globus pallidus (GPe) was hyperactivated, or showed a much higher level of neuron activity.
The researchers then chemically inhibited the neurons in the GPe, which actually reduced disadvantageous risk-taking activity in the mice. This proved that hyperactivation of the GPe was indeed responsible for poor decision-making in the mice treated with PPX.
This study has huge implications for treating patients with Parkinson’s disease.
“Our findings could lead to the development of new medications or interventions that specifically target the external globus pallidus,” explains Dr. Kubota. ‘This would help to prevent or reduce decision-making impairments in Parkinson’s disease patients.’
Besides helping medical professionals develop better treatments for Parkinson’s disease, these findings can also help improve awareness among affected patients, their families, as well as the general public.
Dr. Kubota, explains that “Investigating how Parkinson’s disease medications affect decision-making will help the public to better understand the complexity of the disease and its treatment.”
He also says “This will benefit patients, their families and carers, and motivate them to consider early care and preventive strategies.”
These findings shed new light on the complex processes in the brain that aid our everyday decision-making skills, and promise to improve quality of life for patients affected by Parkinson’s disease.
Maybe we can take away some important lessons from this study as well, and think twice before we indulge in poor decision-making in our daily lives.
About this Parkinson’s disease and neuropharmacology research news
Author: Hisatsugu Koshimizu
Source: Fujita Health University
Contact: Hisatsugu Koshimizu – Fujita Health University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson’s Disease” by Hisayoshi Kubota et al. International Journal of Molecular Sciences
Abstract
Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson’s Disease
In patients with Parkinson’s disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive.
Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making.
PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task.
This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices.
These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice.
The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.
