Researchers discover how patients can get addicted to levodopa
Levodopa leads to hyperactivation of neurons expressing dopamine D1 receptor
Researchers have identified a mechanism underlying an addiction-like psychiatric complication of levodopa treatment known as dopamine dysregulation syndrome (DDS) in people with Parkinson’s disease in a recent preclinical study.
In a mouse model, a DDS-like state was associated with abnormal activation of a certain population of nerve cells (neurons) expressing a protein called the dopamine D1 receptor (D1R). Blocking or inactivating D1Rs reversed the addictive behaviors in the mice.
“We have identified a mechanism at the basis of DDS,” Gilberto Fisone, PhD, professor at the Karolinska Institutet in Sweden and the study’s senior author, said in a university press release. “We found that … treatment with Levodopa leads to abnormal activation of a specific group of neurons located in the brain rewarding system and involved in the effects of addictive substances.”
The study, “Rewarding properties of L-Dopa in experimental parkinsonism are mediated by sensitized dopamine D1 receptors in the dorsal striatum,” was published in Molecular Psychiatry.
In Parkinson’s disease, neurons responsible for producing the brain signaling chemical dopamine are progressively damaged and lost. Dopamine is critical for motor control as well as several other brain functions, including mediating feelings of reward, pleasure, and motivation.
Dopamine-replacing medications typically used in Parkinson’s
Dopamine-replacing medications, including the gold-standard levodopa, are the mainstay treatments for the neurodegenerative disease.
While these medications are effective for controlling the motor symptoms of Parkinson’s, they can also lead to serious motor and nonmotor side effects. Perhaps the most well-recognized and well-studied is dyskinesia, or uncontrolled and involuntary movements that often arise with long-term levodopa use.
A less common nonmotor complication of dopamine therapies is DDS, which occurs in around 5% of patients. With DDS, patients take on an almost addiction-like dependence to these medications. This causes them to take far more than they need to control their symptoms.
“Patients with DDS feel under-medicated, ignore recommended dosing schedules and self-medicate to a level that often leads to further complications, such as dyskinesia,” Fisone said.
Compared with dyskinesia, this consequence of Parkinson’s treatment hasn’t been well-studied, and scientists don’t fully understand how it occurs.
In the recent study, researchers sought to learn more about the cellular basis of DDS using a mouse model of Parkinson’s where a toxic chemical is injected into the brain to deplete dopamine levels.
They found that when treated with levodopa, Parkinson’s mice showed behavioral signs of an addictive-like state consistent with DDS, whereas this did not happen in healthy mice treated with levodopa.
Dopamine loss in brain needed for levodopa to become addictive: Researchers
This indicates that the loss of dopamine in the brain, as occurs in Parkinson’s, is necessary for levodopa to become addictive to patients, according to the researchers.
Behavioral changes in these animals were accompanied by abnormal and excessive signaling of a group of neurons expressing D1Rs, a protein that’s involved in mediating dopamine’s role in reward and addiction. This population of cells was seen specifically in a brain region called the dorsal striatum.
Abnormal D1R neuron signaling was associated with overactivation of a number of signaling cascades, including increased levels of delta-FosB, a protein known to be involved in regulating gene activity during addiction.
Treatment with a chemical to block D1Rs reversed those effects and signs of DDS-like behavior in the Parkinson’s model. Similar effects were observed with a genetic intervention to inactivate D1Rs.
“Taken together, these findings provide the first evidence of a causal link between abnormal activation of D1R-expressing [neurons] and [levodopa]-induced addictive-like behavior,” the researchers wrote.
As such, the findings suggest “therapeutic approaches targeting excessive D1R-mediated transmission may be beneficial for the treatment of DDS,” the team concluded.
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