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What insights into the role of personality and addiction have been obtained from the study of the behavioural effects of dopamine receptor agonists in Parkinson's disease patients?
Parkinson's disease has always been a mystery; its precise cause is unknown. It is believed to be either environmental, genetic or a combination of both factors. What is more of mystery is that once PD patients are put on dopamine agonists that is supposed to restore the levels of the depleted dopamine in the brain regions, some of them seem to develop this dramatic addiction to their medication and exhibit a shift in personality. Some also start gambling or become addicted to it, despite being aware of the negative consequences of their actionsâ€¦still they persist. This is believed to be caused by the medication and its effect on dopamine in the brain. After assessing the major underlying factors believed to be responsible, I concluded that just like the cause of the disease, a combination of factors could be responsible for this mystery; elevated dopamine levels alone was not sufficient a reason. A combination of increased expression of D3 receptors in the brain and the DA (Dopamine agonists) drug pramipexole could be the solution to this mystery.
Keywords: Parkinson's Disease, Dopamine agonists, Gambling, Addiction, D3
Chapter 1: Introduction
There are several diseases of the brain, such as CJD and Alzheimer's but only a few cause the loss of neurons. One of the best known of this type is Parkinson's disease. It affects about 1% of people over the age of 50 (Bear et al, 2001)
Its major symptoms are characterized by hypokinesia ; this involves slowness in movement (Bradykinesia), tremors in hands and jaw and ( akinesia) difficulty initiating movement. (Bear et al, 2001)
In his essay "Essay of the Shaking Palsy", Physician James Parkinson first enlightened the world of this movement disorder by describing its general characteristics. Very little was known about Parkinson's disease (PD) then, but through research and better resources, we now know a lot more but still not enough to find a cure.
Parkinson's disease affects neurons in a part of the brain called the substantia nigra. These neurons mainly produce the neurotransmitter Dopamine, in Parkinson's, up to 80% of these neurons may be non-functional and this declines the striatal dopamine levels by up to 80% of its normal levels. (Meyer. J.S. and Quenzer, L.F,1997) which causes the symptoms Dr J Parkinsons originally identified (Parkinson's J. 2002).
Fig 1: Dopaminergic system showing the substantia nigra.
F:\project final draftsss\2010-04 (Apr)\2010-04 (Apr)\scan0002.jpg (Taken from Bear et al, 2001)
The main aim of most therapies for Parkinson's disease is to enhance the level of dopamine being produced by the remaining cells in the substantia nigra, this was initially done by using a precursor of dopamine called L-Dopa but its effectiveness is reduced after awhile. That led to the development of Dopamine agonists such as Pramipexole and Ropinirole as alternative treatment. Oddly, it has been found that some patients develop personality and behavioural changes such as pathological gambling and hyper-sexuality (Dagher, A and Robbins. TW. 2009) as a result of the medications they are taking. However, this phenomenon appears only in about 8% of PD patients. (Ferris J, 1996)
Figure 2: The diagram below shows neuron releasing dopamine from the ventral tegmental area (VTA). The dopamine acts on the D1 and D2 receptors on the neuron in the nucleus accumbens (NA)
(Taken from Trevor W. Robbins & Barry J. Everitt, 1999)
Chapter 1.1: Parkinson's disease: How, what and why?
It's believed that oxyradical- induced oxidative stress is responsible for the damage caused to dopamine neurons in the brain. Oxyradicals are very reactive and if allowed to build up, they can cause damage to the neurons. (Meyer. J.S. and Quenzer, L.F,1997)
Histopathological examination of the brains of PD patients revealed that degeneration or loss of neurons in the substantial nigra was the root of Parkinson's disease. Substantia nigra means "black substance" because it appears black but in PD patients the loss of pigmented neurons means this black substance is no longer black when stained (Fig 6) (Meyer. J.S. and Quenzer, L.F,1997)
Dopamine is extremely important because of its role in the brain. The striatum, substantia nigra and other structures in the brain make up the Basal ganglia, which with the help of dopamine, acts as a gate that controls movement commands. Therefore when dopamine levels have declined, it becomes extremely difficult for the basal ganglia to initiate voluntary movements. (Meyer. J.S. and Quenzer, L.F,1997)
Chapter 1.2: Identifying the Possible Causes
These developments are somewhat unexpected because most of the patients that develop these changes in personality and behaviour are usually people that do not usually gamble, drink or smoke. Their normal personality type is of total opposite to that which they develop during the duration of their medication.(Todes and Lees, 1985)
The underlying mechanism by which these changes develop is still under scrutiny. A specific drug; Pramipexole has been shown to be the medication most predominantly implicated and also appears to be the most prescribed drug (Szarfman A, 2006). But, what makes this drug different from the others and how does it cause these changes - if it does?
Some patients were also found to be taking a higher than maximum licensed dose of the Dopamine agonists (Gallagher, D.A et al 2007). Could it be that over stimulation of dopamine receptors are causing these changes in the patients or are there other factors involved?
This project aims to assess the underlying cause of this phenomenon and to determine how dopamine agonist drugs are involved.
Fig 3: Shows some of the brain structures
affected by drugs of abuse.
(Taken from: Trevor W. Robbins &
Barry J. Everitt, 1999)
Chapter 2: Dopaminergic medication
Pathological gambling is defined as failure to resist gambling impulses despite several personal, family or vocational consequences. This rare complication has been related to the medication used in the treatment of PD (Evans AH et al 2004)
The type of dopaminergic therapy used to treat PD patients includes dopamine agonists. Dopamine agonists are drugs that mimic the action of dopamine in the brain. Commonly, a medication called Levadopa or L-dopa was the main drug used to treat PD patients but as of the 1980s, it was reported that there were some cases of Levadopa addiction in some patients being treated with Levadopa. (Giovannoni et al., 2000)
The characteristics of these patients includes: compulsive drug taking in excess of clinical requirements; persistent use despite social and personal difficulties caused by the drug and hoarding the drug or obtaining prescriptions from different physicians. (Giovannoni et al., 2000). Apart from drug addiction, behavioural changes were also noticed, such as: hypersexuality, compulsive shopping, pathological gambling and compulsive eating. (Dodd et al., 2007)
What makes pathological gambling a complication in PD patients is that it was found in a review by Gallagher et al.,2007 that PD patients taking DA drugs are up to eight times more likely to develop pathological gambling than the general population (Gallagher, D.A et al 2007). Thus implicating that this prevalence is likely to be drug or dose related and further supporting the association between dopamine agonist and pathological gambling (PG). In terms of the general population, not many people who have ICDs (Impulse Control Disorders) are willing to present themselves to a clinic to be available for screening or even ledge it (Weintraub, D. et al 2006). Therefore, there might not actually be a difference between the prevalence of pathological gambling in PD patients and the general population.
The striking observation in this remarkable situation is that despite many of the patients with PD being treated with a large variety of DA drugs, only an estimated 8% of these patients actually develop a change in behaviour, leaving the question; why not all the PD patients? This has led to the belief that there must be other underlying factors such as neurobiological or genetic predisposition that leads to the observed changes in behaviour (Gallagher, D.A et al 2007).
Fig 4: This shows 11 different patients with PD, with their history of gambling before and after starting medication. It also shows the latency period before they developed gambling and how soon the gambling resolved after they discontinued the medication.
(Taken from Dodd, M.L., et al 2005)
Dopamine agonists were believed to be the main cause of pathological gambling, most notably Pramipexole. This dopamine agonist seems to have a high affinity for the dopamine receptor D3 in the brain, whilst most dopamine agonists are selective for dopamine receptor D1. Therefore, it was believed that the stimulation of this D3 receptor might be responsible for the occurrence of pathological gambling in PD patients. (Dodd, M.L et al 2005)
It has been reported in several case studies that the reason Pramipexole is more commonly associated in the development of PG is due to it being relatively more prescribed than the other DA drugs. An FDA (Food and Drug administration) audit provided evidence for this; Pramipexole being >55% of DA drugs prescribed. (Gallagher, D.A et al 2007)
In a database of food and drug administration adverse events, 67 reports of pathological gambling identified Pramipexole as the culprit in 58% of the cases. (szarfman et al., 2006) However, this relationship between dopamine agonists and PG was not originally accepted, the report was believed to be biased because of the earlier publications linking Pramipexole to pathological gambling. In 2007, Gallagher et al reviewed all previous published case studies and found that out of 177 PD patients, 98% were taking the dopamine agonist. (Gallagher et al., 2007)
Fig 5. This table shows 17 patients from 6 different sources, showing that all patients with PD and pathological gambling were taking a dopamine agonist, mostly Pramipexole.
(Taken from Dodd, M.L., et al 2005)
Chapter 3: The Cases
Pathological gambling is believed to be more likely to occur in young male patients with a pre-morbid history of alcohol abuse (Evans et al., 2005; Voon et al., 2007). This has therefore influenced the selection criteria for case studies as young males PD patients are likely to be selected. This limits how general and reliable the results are. A more systemic analysis should be undertaken to obtain a more generalised view. Pathological gambling is believed to arise after the introduction of new dopaminergic medications, most importantly DA drugs; adding further evidence to the belief that DA drugs are very much implicated in the development of these behavioural changes.
Fig 6: shows damage to the nigrostriatal pathway on one side of the brain.
F:\project final draftsss\2010-04 (Apr)\2010-04 (Apr)\scan0020.jpg
(Taken from Meyer. J.S. and Quenzer, L.F,1997)
To examine the relationship between pathological gambling and these dopamine agonist drugs, (Dodd, M.L et al 2005) observed 11 patients with PD. In this study, Pramipexole was the drug used in treating 9 of the 11 cases and Ropinirole in the other 2 cases. Seven of these 11 patients developed pathological gambling within the first 3 months, but this developed in the other 4 patients about 12-30 months later. In 8 of the patients, there was a cessation in the gambling once the dopamine agonist drug therapy was stopped. When Levadopa was used alone, none of the patients developed any problems. It should be noted that some of the patients were taking a dose of dopamine agonist that was higher than normal (Dodd, M.L et al 2005).
Other case studies have further cemented the notion that treatment with dopamine agonists are a frequent cause of pathological gambling. Nine patients with a case of pathological gambling were observed by Driver-Dunckley et al, it was found that 8 of these patients were being treated with Pramipexole. (Weintraub, D. et al 2006)
Chapter 4: Dose and Sensitization
The relationship between the development of behaviour changes in PD patients and dopamine agonist drugs could be dependent on the dose. It was discovered that patients with these changes in behaviours (behaviours which is now classified as ICDs (Impulsive Compulsive Disorders)) were being treated with dopamine agonists doses that were higher than the normal therapeutic range. Implicating that maybe the underlying cause is dose related and not specifically to certain types of dopamine agonist. (Weintraub, D. et al 2006)
It was observed that before the PG surfaced in some PD patients, they were on a stable dose for several months. (Gallagher, D.A et al 2007) Other factor believed to contribute to this phenomenon is sensitization; this is an increased effect of stimulation with repeated administration of certain drugs (Paulson, P.E and Robinson T.E, 1995).
Evans et al (2006) measured the level of dopamine released in PD patients after a single dose of Levadopa. This was done in patients with and without addiction to their medication using positron emission tomography (procedure that measures metabolic activity of the cells of body tissues.). It was found that dopamine was released equally in the motor striatum of both groups but in the VStr (Ventral Striatum), there was significant dopamine release in the addicted group, indicating a neurological factor of sensitization. (Nelson and Killcross, 2006)
Fig 7 Interactions of the Mesocortical and Mesolimbic Circuits in Drug Addiction
(Taken from Goldstein, R.Z., and Volkow, N.D. (2002)
4.1: Dopamine and the Ventral Striatum
The key site where drugs cause addiction seems to be where the dopamine neurons project axons through to the forebrain in the Ventral tegmental area of the brain. (Bear et al, 2001)
The role of dopamine in causing changes and motivation in behaviours is still unclear but there have been some indication that any behaviour that is in conjunction with the provision of drugs that causes the release of dopamine in the nucleus accumbens is a motivation factor for some animals and this behaviour is then sustained. (Bear et al, 2001)
Dopamine receptor agonists are a group of compounds that do not require metabolic conversions as they provide their effects by acting directly on the dopamine receptor. A major pharmacological difference between L-dopa and most dopamine receptor agonists used in the treatment of PD is that agonists have longer plasma half-life than L-dopa. Assuming that plasma concentration predicts what occurs in the striatum, it is reasonable then to consider that a dopamine like agent with a long plasma half-life will induce more continuous stimulation of striatal dopamine receptors than a dopamine like agent with a short plasma half life. Numerous experimental studies have demonstrated that this is the case in Parkinsonian monkeys. (Olanow C.W et al 2000)
The behavioural changes seen in PD patients and also the medication addiction has been associated with one of the symptoms of PD; dyskinesia. These involuntary movements are due to excessive dopamine levels. The addiction and behavioural changes seem to reduce with reduction in DA medication, indicating that the DA drugs may be causing a higher than normal dopamine neurotransmission in the brain. (Dagher, A and Robbins. TW. 2009)
Burton et al., (2004) found in there research that some PD patients suffer from frontal lobe atrophy and gray matter loss. If it could be determined that addicted PD patients suffer this frontal lobe atrophy then this can provide more information but this hasn't been the case so far (Burton et al., 2004)
Fig 8: Shows stained section of a PD patient and normal person in the substantia nigra.
F:\project final draftsss\2010-04 (Apr)\2010-04 (Apr)\scan0003.jpg
(Taken from Meyer. J.S. and Quenzer, L.F,1997)
Goldstein and Volkow, (2002) identified by neuropsychological testing and imaging, frontal abnormalities in medication addicted individuals and pathological gamblers. Also, similar behaviours have been described in patients suffering from frontal lobe variant of fronto-temporal dementia (Lo Coco and Nacci, 2004; Passant et al., 2005)
Fig. 9 Atrophy in Parkinson's disease patients show (A) compensated for differences in head size, with significant grey matter loss observed in the right frontal lobe and (B) as regional changes in grey matter, above that occurring globally, with less significant changes in the right frontal lobe.
(Taken from Burton, E.J., et al 2004)
Chapter 5: The D3 receptor
Dopamine has 5 subclasses of receptors; D1 - D5, they act through second messengers. These receptors can be found in the striatum and nucleus accumbens. The D2, D3 and D4 receptors are similar to each other, whilst the D1 and D5 receptors are different to the others. (Meyer. J.S. and Quenzer, L.F,1997)
A dopamine receptor that is believed to be implicated in sensitization is the D3 receptor; it is expressed primarily in the VStr and limbic system, a region activated by most addictive drugs. (Gardner, 2005). Of all the Dopamine receptors, the D3 receptor has the highest affinity for DA drugs within the brain (Sokoloff et al, 1992) Levant, 1997).
In the treatment of animal models of PD, it becomes up-regulated in response to Levodopa (Bordet et al.,1997) and also in drug addicts at post-mortem. This D3 receptor, in animals, has shown to increase the motivation to obtain drugs even when the cost is high (Le Foll et al., 2005; Bickel et al., 2000).
D3 receptors in PD patients are expressed more than normal by the striatal neurons because some have this significant loss of midbrain. Dopamine agonist drugs usually act on D1 and D2 receptors but the neurons that usually express these receptors express more of the D3 receptors in PD patients. (Bordet et al.,1997).
Fig 10: Signalling mechanism for D1 and D3 receptors.
F:\project final draftsss\2010-04 (Apr)\2010-04 (Apr)\scan0022.jpg (Taken from Meyer. J.S. and Quenzer, L.F,1997)
It is also quite astonishing that Pramipexole has a higher affinity for this D3 receptor than other dopamine receptors. These developments are painting a picture of the reason why some PD patients develop this medication addiction and behavioural change. The role of D3 receptor has not been proven yet and the implication of dopamine agonist such as Pramipexole has only been confirmed in small meta-analyses (Gallagher et al., 2007)
D3 receptors were evaluated in animal models of addiction as a target for the development of medication against drug addiction (Heidbreder et al, 2005) but, it was hard to assess their effectiveness in vivo. Eventually, some D3 partial agonists and antagonists were developed, such as SB-277011A (Le Foll et al, 2000). It was found to inhibit drug seeking behaviours and rewarding effects of drugs (Vorel et al, 2002). If the results obtained in animal models could be replicated in human addicts, the D3 receptor antagonists could potentially provide the path to provide effective medication against drug addiction.
Chapter 6: Conclusion
The evidence supporting the association between dopamine agonist and the development of addiction is quite strong but the neurobiological mechanisms involved are poorly understood. Several case studies and reports appear to link the DA drugs to the mystery of addiction, mainly pathological gambling.
At the centre of it all is 'Dopamine' because this is what is missing in PD patients and it is what the DA drugs are attempting to restore in the limbic region of the brain (Goldstein, R.Z. et al 2002).
It is possible that the medication does not just restore the levels of dopamine in the dorsal striatum back to normal, but they may also over stimulate and produce too much dopamine. However, an increase in dopamine alone is inadequate to cause addiction, therefore there must be a combination of structural and neurological changes.
Pramipexole has been the most prescribed drug to PD patients according to most case studies. This means that it is more likely to be blamed for the changes seen as it is over-represented. However, most of the prescribed dopamine agonists have been associated with pathological gambling, therefore there is a high chance that the consistency of Pramipexole being prescribed correlates with it being implicated as the culprit.
Pramipexole does seem to have a high affinity for the D3 receptor, which is another major factor. This carries the most weight in terms of evidence in support of why some people develop this addiction and others do not. It is shown that some patients suffer frontal lobe atrophy, therefore exposing more of the D3 receptors in that region of the brain where dopamine acts.
If the patient is prescribed a drug with a high affinity for this receptor, then the likelihood of addiction occurring increases. A combination of the drug Pramipexole and the D3 receptor could be the underlying cause of this deep mystery though the evidence is quite inadequate. I believe that the contribution of the D3 receptor warrants further attention. There is undoubtedly a lot left to learn in how the PD patients on DA medication develop these changes, further still to learn about how dopamine agonists affect the brain of PD patients.
Management and Future Perspectives
As it was found that a lot of PD patients were taking a higher than normal dose of DA drugs, this should clearly be rectified and avoided. Clinicians should be more alert and aware, probing questions should be asked of the patient's habits in order to avoid further complications. Maybe switching between different DA drugs might be beneficial and could decrease the onset of addiction symptoms so the brain does not get too used to it. (Gallagher, D.A et al 2007)
Individuals most at risk should also be identified and screened by either questionnaires or via taking relevant information such as drug use and gambling history. Further study should also be carried out to investigate if specific populations are more at risk. (Dorom Merims and Nir Giladi 2008.)
Self-help group should be created to help individuals who are suffering from such addiction, a group not for the general population but specifically for PD patients.
Glossary of Terms
Basal Ganglia: A series of four neurone clusters which are responsible for transmitting information from cerebral cortex to the brain stem and cerebellum, in order to modulate body motor movements.
Dopamine: A monoamine neurotransmitter derived in parts of the brain that govern movement and emotions.
Neurotransmitters: Natural nerve chemicals that communicate between neurones by transmitting nerve impulses from one cell to another.
Receptors: Molecules usually expressed on the cell surface (there are some intracellular receptors), where particular messenger molecules (i.e. neurotransmitters) can bind in a lock-and- key mechanism.