Pramipexole side effects linked to overactive brain region in study
Research in mice may explain some effects of Parkinson’s drug Mirapex
Pramipexole, the active ingredient in the Parkinson’s disease therapy Mirapex, appears to overactivate a brain region known as the external globus pallidus — findings that could explain the poor decision-making and impulse control that occurs as a side effect of the medication in some patients — according to a study in a mouse model.
“Our findings could lead to the development of new medications or interventions that specifically target the external globus pallidus,” Hisayoshi Kubota, an assistant professor at Fujita Health University in Japan, said in a university press release. “This would help to prevent or reduce decision-making impairments in Parkinson’s.”
The researchers say they hope their work in this mouse model of Parkinson’s will help to improve overall awareness of the complexity of the disease in people, as well as the difficulties of treating it.
“Our findings implicate hyperactivation of [this brain region] … as a candidate neural mechanism by which [therapies like pramipexole] can lead to decision-making impairments,” the researchers wrote. “The current study represents a significant step toward the development of clinical strategies for maintaining the therapeutic efficacy of [pramipexole and other similar Parkinson’s medications] while reducing their adverse effects.”
The study, “Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson’s Disease,” was published in the International Journal of Molecular Sciences.
Mice show similar pramipexole side effects to humans
Parkinson’s is caused by the loss of dopaminergic neurons — nerve cells in the brain that produce the chemical messenger dopamine, needed to control movement. This causes motor symptoms, such as tremor, stiffness, slowness, and impaired balance, that worsen gradually over time.
Medications, such as dopamine receptor agonists, can help manage motor symptoms. However, some of these treatments can lead to previously unexplained side effects related to decision-making and impulse control, including binge eating and urges to gamble or spend money. The exact reasons for these side effects are unclear, according to the researchers.
“Investigating how Parkinson’s disease medications affect decision-making will help the public to better understand the complexity of the disease and its treatment,” said Kubota, the study’s first author. “This will benefit patients, their families and carers, and motivate them to consider early care and preventive strategies.”
To explore the reasons for these side effects, the researchers turned to a mouse model of Parkinson’s. The mice were treated with pramipexole, a medication that mainly activates a type of dopamine receptor called D3, and tested for their ability to make decisions using the Iowa Gambling Task. This test can be used to study decision-making when there’s some uncertainty or risk involved.
Investigating how Parkinson’s disease medications affect decision-making will help the public to better understand the complexity of the disease and its treatment. … This will benefit patients, their families and carers, and motivate them to consider early care and preventive strategies.
Compared with healthy mice or mice treated with a placebo, those treated with pramipexole made more disadvantageous decisions, and made them more often. The treated mice were found to be more likely to choose high-risk options that offered big rewards but were ultimately harmful as they increased the risk of punishment by exposure to flashing lights.
In the brain, treatment with pramipexole increased the number of active cells in the external globus pallidus, a region involved in the control of movement and decision-making. After the scientists used a technique called chemogenetics to selectively turn off this region, brain activity returned to normal and the mice stopped making disadvantageous decisions.
“Our findings pinpoint a neural circuit involved in decision-making and a candidate therapeutic target for [pramipexole]-induced pathological [disease-related] gambling,” the researchers concluded. Targeting the dopamine D3 receptor or the external globus pallidus could help prevent these side effects, the team noted.
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