How Parkinson’s Drug Levodopa Causes Psychiatric Complications Similar to Drug Addiction

Researchers at Karolinska Institutet have identified a mechanism responsible for a serious psychiatric complication caused by dopamine replacement therapy in Parkinson’s disease. The results of this research were recently published in Molecular psychiatry.

Treatment of Parkinson’s disease relies largely on the administration of levodopa. The use of this drug is limited by the development of psychiatric complications, including a disorder similar to drug addiction called dopamine dysregulation syndrome (DDS).

“We have identified a mechanism underlying DDS. We found that, in an experimental model of Parkinson’s disease, levodopa treatment leads to abnormal activation of a specific group of neurons located in the brain’s reward system and involved in the effects of addictive substances,” explains Gilberto Fisone, professor in the Department of Neuroscience and lead author of the study.

The resulting change in transmission leads to dysregulation of specific proteins involved in neuronal function, which represent a potential target for interventions aimed at combating psychiatric disorders in patients with Parkinson’s disease.

DDS affects about five percent of Parkinson’s disease patients treated with levodopa and involves pathological overuse of medication, well beyond what is needed to correct the motor symptoms of the disease.

“Patients with DDS feel undermedicated, ignore recommended dosing regimens, and self-medicate to a level that often leads to other complications, such as dyskinesia,” Fisone says.

Down syndrome is a major concern for patients and their families. However, the mechanisms involved in this disorder are poorly understood. The identification of a specific set of neurons pathologically affected by levodopa and causally linked to addictive behavior provides this information, paving the way for the future identification of measures to improve the treatment of Parkinson’s disease.

The study was based on the use of a rodent model of Parkinson’s disease that recreates its complex pathology. The researchers discovered that the addictive effect of levodopa was due to its ability to hyperactivate a group of neurons expressing the dopamine D1 receptor (D1R) in the basal ganglia.

The next step is to investigate the possible involvement in DDS of Delta-FosB, an important regulator of gene expression involved in drug addiction. Delta-Fos B levels are increased in D1R-expressing neurons after levodopa administration.

“Our hypothesis is that by controlling Delta-FosB overexpression through genetic intervention, we can also counteract DDS,” Fisone says.