By Sheel Patel, published in our 2015-16 issue

Approximately seven to ten million people are living with Parkinson’s disease (PD) worldwide, according to the Parkinson’s disease Foundation. Parkinson’s disease is an age related movement disorder that is characterized by decreased levels of Dopamine (DA) in the striatum of patients due to deterioration and atrophy of nigrostriatal dopamine neurons (Jankovic, 2008). There are four major clinical features of Parkinson's disease that are tremor at rest, rigidity, akinesia, and postural instability (Jankovic, 2008). These symptoms are usually a result of the decreased dopaminergic tone in the caudate, putamen, substantia nigra, and other dopaminergic system nodes (Nagatsu et. al, 2008). PD is often associated with other cognitive symptoms like depression, anxiety, sleep disorders, and in some cases impulse control issues (DeLong et. al, 2007). With millions suffering from the physical and cognitive toll Parkinson’s takes, treatment options are crucial to maintaining a positive quality of life in patients. Through the advancement of medical research in recent years, physicians treating patients with Parkinson’s have options ranging from deep brain stimulation (in severe cases) to medications like Levodopa, the latter being considered “the gold standard” by many physicians. Levodopa therapy brings a relief of symptoms for many patients suffering from PD, however there are often costly physical and cognitive side effects that create new issues.

In 1957, a seminal discovery by Arvid Carlson and his colleagues led to the discovery of dopamine and its importance in the occurrence of Parkinsonian symptoms. Symptoms were shown with the administration and study of the drug reserpine. Reserpine was found to block the vesicular monamine transporter (VMAT), preventing dopamine and the monoamines from entering vesicles and subsequently being released into the synapse. Depletion of dopamine by reserpine produced Parkinson like akinesia in animals, and supplementation of the deficient dopamine by L-dopa administration ameliorated the movement disorder (Carlsson, 2002). Along with the discovery of dopamine and its role in PD, new research techniques have shown that circuitry deficits that may cause the onset and progression of this disease. Through imaging studies in animal models of Parkinson’s disease, researchers have developed a model of basal ganglia dysfunction leading to symptoms. It is believed that Parkinson’s is related to an increased activation of the indirect basal ganglia pathway and decreased activation of the direct pathway. This corresponds to increased inhibition of the globus pallidus external segment (GPe), disinhibition of the substantia nigra (STN), and increased excitation of of the globus pallidus internal segment (GPi) and substantia nigra pars reticulata (SNr), which make up the indirect pathway. This also corresponds to a net decrease in activation of the direct striatal pathway (DeLong et. al, 2007). Therefore, Parkinson’s disease appears to result from an imbalance of the direct and indirect stratal pathways, causing a decrease in dopaminergic tone and subsequently the symptoms of the disease.

L-dopa and its method of action

With Arvid Carlsson’s study using reserpine, he found that PD akinetic symptoms were alleviated with supplementation of DOPA. Along with this finding, Carlsson also noticed that recovery of function was specifically correlated to the recovery of dopamine in the brain compared to the other monamines, noradrenaline and serotonin (Carlsson et. al, 1957). Today, this is done through supplementation of levodopa (L- dopa). L-dopa serves as an efficient treatment for dopamine deficiency due to its role as a precursor to dopamine in the brain. In order to synthesize dopamine in the brain, the amino acid tyrosine is needed. Tyrosine is converted into L-3,4-dihydroxyphenylalanine (L-dopa) by the enzyme tyrosine hydroxylase. Once L-dopa enters the central nervous system, it is converted into dopamine by the enzyme DOPA decarboxylase (aromatic L-amino acid decarboxylase). This dopamine can then be used as a neurotransmitter in various areas of the central nervous system (Riderer et. al, 2001). Dopamine can also be further processed to produce the other catecholamines, norepinephrine and epinephrine.

Exogenous L-dopa treatment, as pioneered by Carlsson, is not used often in Parkinson’s patients due to the , nigro-striatal neuronal degradation that leaves patients without the ability to use DOPA decarboxylase and tyrosine hydroxylase (TH) to enzymatically render tyrosine and L-dopa into dopamine, which can be used in nerve terminals (Nagatsu & Sawada, 2007). L-dopa is also efficacious through the neurons and glial cells, other than dopamine neurons, in the striatum such as serotonin neurons and noradrenergic neurons which contain TH and DOPA decarboxylase. These neurons and glial cells can take the exogenous L-dopa given in treatments and convert it into dopamine, to supplement the deficiency due to PD (Huot et. al, 2007). Through the discovery of L-Dopa and its ability to supplement dopamine levels, clinical trials have shown its ability to directly impact the lives of PD patients.

L-dopa clinical treatment and side effects

A major breakthrough in using L-dopa as treatment for PD patients came in 1969. Cotzias et al. . were the first to demonstrate L-dopa’s efficacy in a clinical setting by administering larger oral doses of the drug to patients with PD in order to produce an adequate amount of dopamine in the brain (Cotzias et. al, 1969). With the treatment, Cotzias’s patients showed signs of improvement from their symptoms. The symptoms were mitigated in a specific order with the loss of akinesia, then rigidity, and finally tremor. These trials were confounded with unexpected cognitive side effects with patients experiencing a marked amelioration of outlook, general well being, and improved memory.

Along with the decrease in symptoms and cognitive improvement, L-dopa therapy often has negative effects. In the case of Cotzias’s patients, involuntary movements were found in 50% of patients, with the most severe movements occurring in patients that had suffered from Parkinson’s for the longest duration of time (Cotzias et. al, 1969). As Cotzias observed, L-dopa therapy sometimes caused the opposite problem in patients, where they were unable to control sporadic movements. This phenomenon has been researched in recent years. Case studies of L-dopa therapy along with other dopamine agonists have shown a pattern of ‘on’ and ‘off’ periods of motor fluctuations after extended treatment. “On” periods generally indicate a period of time when motor fluctuations and tremors are not present, indicating that drug therapy is working. However, patients often experience “off” periods where tremors and involuntary movements return, usually later in the day after taking their medication (Lees, 1989). These symptoms generally begin to occur 2-5 years into L-dopa treatment, indicating their may be a plasticity effect occurring in the brain. Along with these motor side effects, L-dopa therapy often creates cognitive problems for PD patients.

With the prevalence of Dopamine throughout the brain, especially in areas and circuits that comprise the reward system, we can see how treating patients with L-dopa could result in a possible augmentation of the reward system. Dopamine plays a key role in assessing and predicting rewards and addiction (Bressan & Crippa, 2005). Endogenous dopamine is often released into the striatum during the anticipation of a reward, allowing the subject to learn what stimulus predicts a reward (Merims & Giladi, 2007). Changes in this reward system in some PD patients has been documented. One specific syndrome found in some PD patients undergoing dopamine replacement therapy has been called dopamine dysregulation syndrome (DDS). DDS is a neuropsychiatric behavioral syndrome associated with substance misuse and behavioral disturbances that can resemble a hypomanic state or disturbances in the impulse control system resulting in an uncontrolled urge or drive to perform certain acts (Merims & Giladi, 2007). A 2007 study by Merims and colleagues found a connection between Parkinson’s disease and DDS.

When comparing 193 PD patients to 190 age-matched controls, they observed that 14% of the PD patients had heightened interest or drive for being involved in gambling, sexual activity, overeating (with weight gain) and excessive money spending (mainly shopping), compared to 0% of the controls. This showed a significant change in the patients impulse control system, a hallmark of DDS. Patients whom had a younger onset of PD symptoms, were male, and had a longer duration of treatment with dopamine therapies showed additive effects to the risk of developing one of these behaviors (Merims & Giladi, 2007). This directly shows how treating PD with dopamine therapy can often lead to secondary issues that were never present before starting treatment.

These findings of DDS have also led to research directly linking Parkinson’s disease drug therapies and impulsive disorders like gambling addiction. A study conducted by Molina and colleagues, found a link between Parkinson's patients undergoing L-dopa therapy and the onset of gambling addictions. Of the twelve Parkinson’s patients they studied, they reported that ten patients began gambling after the onset of PD, and nine of those patients began after the start of L-dopa therapy (Molina et. al, 2000). Eight patients gambled only during ‘on’ periods of their treatment, when their symptoms were under control. These patients clearly stated that they had no inclination to gamble during their ‘off’ periods, where they often suffered from motor fluctuations (Molina et. al, 2000). The fact that increased desire to gamble occurred when patients were on their ‘on’ periods suggests that an increase in dopaminergic tone, through treatment, may be a factor for the excess impulsivity, a symptom that was not present before the onset of their Parkinsonian symptoms and therapy.

Conclusion

With L-dopa administration being the “gold standard” of Parkinson’s treatment today, it’s easy to see the relief it allows PD patients to feel. Parkinson’s a disease, characterized by tremors and rigidity, can abrupt the quality of life in the most resilient of patients. Therefore finding a treatment that can improve PD patient’s lives while avoiding the negative side effects, shown with L-dopa, is crucial to future treatments. Recent research has aimed just that with new strategies being developed to administer L-dopa with gene therapy, providing an individual treatment aimed at allowing neurons in the individual to produce endogenous DOPA decarboxylase and slowly require less exogenous L-dopa (Eberling et. al, 2008). This is being studied through introducing the human AADC gene, which produces DOPA decarboxylase, into the the striatum through a virus vector. Through this treatment, the expression of the AADC gene can be controlled by the specific dosage of L-Dopa. This allows extremely personalized therapy for Parkinson’s that can lead to better outcomes for patients.  Advancements like these look promising for the future of PD treatments and bring a new wave of hope in fighting this debilitating disease.

Citations:

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