What insights into the function of personality and dependence have been obtained from the survey of the behavioral effects of Dopastat receptor agonists in Parkinson ‘s disease patients?

Parkinson ‘s disease has ever been a enigma ; its precise cause is unknown. It is believed to be either environmental, familial or a combination of both factors. What is more of enigma is that one time PD patients are put on Dopastat agonists that is supposed to reconstruct the degrees of the low Dopastat in the encephalon parts, some of them seem to develop this dramatic dependence to their medicine and exhibit a displacement in personality. Some besides start chancing or go addicted to it, despite being cognizant of the negative effects of their actionsaˆ¦still they persist. This is believed to be caused by the medicine and its consequence on Dopastat in the encephalon. After measuring the major implicit in factors believed to be responsible, I concluded that merely like the cause of the disease, a combination of factors could be responsible for this enigma ; elevated Dopastat degrees entirely was non sufficient a ground. A combination of increased look of D3 receptors in the encephalon and the DA ( Dopamine agonists ) drug pramipexole could be the solution to this enigma.

Keywords: Parkinson ‘s Disease, Dopamine agonists, Gambling, Addiction, D3

Receptor, Pramipexole.

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Chapter 1: Introduction

There are several diseases of the encephalon, such as CJD and Alzheimer ‘s but merely a few cause the loss of nerve cells. 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 awkwardness in motion ( Bradykinesia ) , shudders in custodies and jaw and ( akinesis ) trouble originating motion. ( Bear et al, 2001 )

In his essay “ Essay of the Shaking Palsy ” , Physician James Parkinson foremost enlightened the universe of this motion upset by depicting its general features. Very small was known about Parkinson ‘s disease ( PD ) so, but through research and better resources, we now know a batch more but still non plenty to happen a remedy.

Parkinson ‘s disease affects nerve cells in a portion of the encephalon called the substantia nigger. These nerve cells chiefly produce the neurotransmitter Dopamine, in Parkinson ‘s, up to 80 % of these nerve cells may be non-functional and this declines the striatal Dopastat degrees by up to 80 % of its normal degrees. ( 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 demoing the substantia nigger.

F: project concluding draftsss2010-04 ( Apr ) 2010-04 ( Apr ) scan0002.jpg ( Taken from Bear et Al, 2001 )

The chief purpose of most therapies for Parkinson ‘s disease is to heighten the degree of Dopastat being produced by the staying cells in the substantia nigger, this was ab initio done by utilizing a precursor of Dopastat called L-Dopa but its effectivity is reduced after awhile. That led to the development of Dopamine agonists such as Pramipexole and Ropinirole as alternate intervention. Curiously, it has been found that some patients develop personality and behavioral alterations such as pathological gaming and hyper-sexuality ( Dagher, A and Robbins. TW. 2009 ) as a consequence of the medicines they are taking. However, this phenomenon appears merely in approximately 8 % of PD patients. ( Ferris J, 1996 )

Figure 2: The diagram below shows neuron let go ofing Dopastat from the ventral tegmental country ( VTA ) . The dopamine Acts of the Apostless on the D1 and D2 receptors on the nerve cell in the karyon accumbens ( NA )

( Taken from Trevor W. Robbins & A ; Barry J. Everitt, 1999 )

Chapter 1.1: Parkinson ‘s disease: How, what and why?

It ‘s believed that oxyradical- induced oxidative emphasis is responsible for the harm caused to dopamine nerve cells in the encephalon. Oxyradicals are really reactive and if allowed to construct up, they can do harm to the nerve cells. ( Meyer. J.S. and Quenzer, L.F,1997 )

Histopathological scrutiny of the encephalons of PD patients revealed that devolution or loss of nerve cells in the significant nigger was the root of Parkinson ‘s disease. Substantia nigger means “ black substance ” because it appears black but in PD patients the loss of pigmented nerve cells means this black substance is no longer black when stained ( Fig 6 ) ( Meyer. J.S. and Quenzer, L.F,1997 )

Dopamine is highly of import because of its function in the encephalon. The striate body, substantia nigger and other constructions in the encephalon make up the Basal ganglia, which with the aid of Dopastat, acts as a gate that controls motion bids. Therefore when Dopastat degrees have declined, it becomes highly hard for the basal ganglia to originate voluntary motions. ( Meyer. J.S. and Quenzer, L.F,1997 )

Chapter 1.2: Identifying the Possible Causes

These developments are slightly unexpected because most of the patients that develop these alterations in personality and behaviors are normally people that do non normally gamble, imbibe or smoke. Their normal personality type is of entire opposite to that which they develop during the continuance of their medicine. ( Todes and Lees, 1985 )

The underlying mechanism by which these alterations develop is still under examination. A specific drug ; Pramipexole has been shown to be the medicine most preponderantly implicated and besides appears to be the most prescribed drug ( Szarfman A, 2006 ) . But, what makes this drug different from the others and how does it do these alterations – if it does?

Some patients were besides found to be taking a higher than upper limit licensed dosage of the Dopamine agonists ( Gallagher, D.A et al 2007 ) . Could it be that over stimulation of Dopastat receptors are doing these alterations in the patients or are at that place other factors involved?

This undertaking aims to measure the implicit in cause of this phenomenon and to find how dopamine agonist drugs are involved.

Fig 3: Shows some of the encephalon constructions

affected by drugs of maltreatment.

( Taken from: Trevor W. Robbins & A ;

Barry J. Everitt, 1999 )

Chapter 2: Dopaminergic medicine

Pathological gaming is defined as failure to defy chancing urges despite several personal, household or vocational effects. This rare complication has been related to the medicine used in the intervention of PD ( Evans AH et Al 2004 )

The type of dopaminergic therapy used to handle PD patients includes dopamine agonists. Dopamine agonists are drugs that mimic the action of Dopastat in the encephalon. Normally, a medicine called Levadopa or L-dopa was the chief drug used to handle PD patients but as of the 1980s, it was reported that there were some instances of Levadopa dependence in some patients being treated with Levadopa. ( Giovannoni et al. , 2000 )

The features of these patients includes: compulsive drug taking in surplus of clinical demands ; relentless usage despite societal and personal troubles caused by the drug and stashing the drug or obtaining prescriptions from different doctors. ( Giovannoni et al. , 2000 ) . Apart from drug dependence, behavioral alterations were besides noticed, such as: hypersexuality, compulsive shopping, pathological gaming and compulsive feeding. ( Dodd et al. , 2007 )

What makes pathological chancing a complication in PD patients is that it was found in a reappraisal by Gallagher et al.,2007 that PD patients taking DA drugs are up to eight times more likely to develop pathological chancing than the general population ( Gallagher, D.A et al 2007 ) . Therefore implicating that this prevalence is likely to be drug or dose related and further back uping the association between dopamine agonist and pathological gaming ( PG ) . In footings of the general population, non many people who have ICDs ( Impulse Control Disorders ) are willing to show themselves to a clinic to be available for testing or even ledge it ( Weintraub, D. et al 2006 ) . Therefore, there might non really be a difference between the prevalence of pathological gaming in PD patients and the general population.

The dramatic observation in this singular state of affairs is that despite many of the patients with PD being treated with a big assortment of DA drugs, merely an estimated 8 % of these patients really develop a alteration in behavior, go forthing the inquiry ; why non all the PD patients? This has led to the belief that there must be other underlying factors such as neurobiological or familial sensitivity that leads to the observed alterations in behavior ( Gallagher, D.A et al 2007 ) .

Fig 4: This shows 11 different patients with PD, with their history of chancing before and after get downing medicine. It besides shows the latency period before they developed chancing and how shortly the gaming resolved after they discontinued the medicine.

( Taken from Dodd, M.L. , et al 2005 )

2.1: Pramipexole

Dopamine agonists were believed to be the chief cause of pathological gaming, most notably Pramipexole. This dopamine agonist seems to hold a high affinity for the Dopastat receptor D3 in the encephalon, 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 happening of pathological gaming in PD patients. ( Dodd, M.L et al 2005 )

It has been reported in several instance surveies that the ground Pramipexole is more normally associated in the development of PG is due to it being comparatively more prescribed than the other DA drugs. An FDA ( Food and Drug disposal ) audit provided grounds for this ; Pramipexole being & gt ; 55 % of DA drugs prescribed. ( Gallagher, D.A et al 2007 )

In a database of nutrient and drug disposal inauspicious events, 67 studies of pathological chancing identified Pramipexole as the perpetrator in 58 % of the instances. ( szarfman et al. , 2006 ) However, this relationship between Dopastat agonists and PG was non originally accepted, the study was believed to be biased because of the earlier publications associating Pramipexole to pathological gaming. In 2007, Gallagher et Al reviewed all old published instance surveies and found that out of 177 PD patients, 98 % were taking the dopamine agonist. ( Gallagher et al. , 2007 )

Fig 5. This tabular array shows 17 patients from 6 different beginnings, demoing that all patients with PD and pathological gaming were taking a dopamine agonist, largely Pramipexole.

( Taken from Dodd, M.L. , et al 2005 )

Chapter 3: The Cases

Pathological gaming is believed to be more likely to happen in immature male patients with a pre-morbid history of intoxicant maltreatment ( Evans et al. , 2005 ; Voon et al. , 2007 ) . This has hence influenced the choice standards for instance surveies as immature males PD patients are likely to be selected. This limits how general and dependable the consequences are. A more systemic analysis should be undertaken to obtain a more generalized position. Pathological gaming is believed to originate after the debut of new dopaminergic medicines, most significantly DA drugs ; adding farther grounds to the belief that DA drugs are really much implicated in the development of these behavioral alterations.

Fig 6: shows harm to the nigrostriatal tract on one side of the encephalon.

F: project concluding draftsss2010-04 ( Apr ) 2010-04 ( Apr ) scan0020.jpg

( Taken from Meyer. J.S. and Quenzer, L.F,1997 )

To analyze the relationship between pathological gaming and these dopamine agonist drugs, ( Dodd, M.L et al 2005 ) observed 11 patients with PD. In this survey, Pramipexole was the drug used in handling 9 of the 11 instances and Ropinirole in the other 2 instances. Seven of these 11 patients developed pathological gaming within the first 3 months, but this developed in the other 4 patients about 12-30 months subsequently. In 8 of the patients, there was a surcease in the gaming one time the dopamine agonist drug therapy was stopped. When Levadopa was used entirely, none of the patients developed any jobs. It should be noted that some of the patients were taking a dosage of dopamine agonist that was higher than normal ( Dodd, M.L et al 2005 ) .

Other instance surveies have farther cemented the impression that intervention with dopamine agonists are a frequent cause of pathological gaming. Nine patients with a instance of pathological gaming 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 behavior alterations in PD patients and dopamine agonist drugs could be dependent on the dosage. It was discovered that patients with these alterations in behavior ( behavior which is now classified as ICDs ( Impulsive Compulsive Disorders ) ) were being treated with dopamine agonists doses that were higher than the normal curative scope. Implicating that possibly the implicit in cause is dose related and non specifically to certain types of Dopastat agonist. ( Weintraub, D. et al 2006 )

It was observed that before the PG surfaced in some PD patients, they were on a stable dosage for several months. ( Gallagher, D.A et al 2007 ) Other factor believed to lend to this phenomenon is sensitisation ; this is an increased consequence of stimulation with perennial disposal of certain drugs ( Paulson, P.E and Robinson T.E, 1995 ) .

Evans et Al ( 2006 ) measured the degree of Dopastat released in PD patients after a individual dosage of Levadopa. This was done in patients with and without dependence to their medicine utilizing positron emanation imaging ( process that measures metabolic activity of the cells of organic structure tissues. ) . It was found that Dopastat was released every bit in the motor striate body of both groups but in the VStr ( Ventral Striatum ) , there was important dopamine release in the addicted group, bespeaking a neurological factor of sensitisation. ( 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 dependence seems to be where the Dopastat nerve cells undertaking axons through to the prosencephalon in the Ventral tegmental country of the encephalon. ( Bear et al, 2001 )

The function of Dopastat in doing alterations and motive in behavior is still ill-defined but there have been some indicant that any behavior that is in concurrence with the proviso of drugs that causes the release of Dopastat in the karyon accumbens is a motive factor for some animate beings and this behavior is so sustained. ( Bear et al, 2001 )

Dopamine receptor agonists are a group of compounds that do non necessitate metabolic transitions as they provide their effects by moving straight on the Dopastat receptor. A major pharmacological difference between L-dopa and most dopamine receptor agonists used in the intervention of PD is that agonists have longer plasma half life than L-dopa. Assuming that plasma concentration predicts what occurs in the striate body, it is sensible so to see that a Dopastat like agent with a long plasma half life will bring on more uninterrupted stimulation of striatal Dopastat receptors than a Dopastat like agent with a short plasma half life. Numerous experimental surveies have demonstrated that this is the instance in Parkinsonian monkeys. ( Olanow C.W et Al 2000 )

The behavioral alterations seen in PD patients and besides the medicine dependence has been associated with one of the symptoms of PD ; dyskinesia. These nonvoluntary motions are due to inordinate Dopastat degrees. The dependence and behavioral alterations seem to cut down with decrease in DA medicine, bespeaking that the DA drugs may be doing a higher than normal dopamine neurotransmission in the encephalon. ( Dagher, A and Robbins. TW. 2009 )

Burton et al. , ( 2004 ) found in there research that some PD patients suffer from frontal lobe wasting and grey affair loss. If it could be determined that addicted PD patients suffer this frontal lobe wasting so this can supply more information but this has n’t been the instance so far ( Burton et al. , 2004 )

Fig 8: Shows stained subdivision of a PD patient and normal individual in the substantia nigger.

F: project concluding draftsss2010-04 ( 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 imagination, frontal abnormalcies in medicine addicted persons and pathological gamblers. Besides, similar behaviors have been described in patients enduring from frontal lobe discrepancy of fronto-temporal dementedness ( Lo Coco and Nacci, 2004 ; Passant et al. , 2005 )

Fig. 9 Atrophy in Parkinson ‘s disease patients show ( A ) compensated for differences in caput size, with important gray affair loss observed in the right frontlet lobe and ( B ) as regional alterations in gray affair, above that happening globally, with less important alterations in the right frontlet 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 2nd couriers. These receptors can be found in the striate body 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 Dopastat receptor that is believed to be implicated in sensitisation is the D3 receptor ; it is expressed chiefly in the VStr and limbic system, a part activated by most habit-forming drugs. ( Gardner, 2005 ) . Of all the Dopamine receptors, the D3 receptor has the highest affinity for DA drugs within the encephalon ( Sokoloff et al, 1992 ) Levant, 1997 ) .

In the intervention of carnal theoretical accounts of PD, it becomes up-regulated in response to Levodopa ( Bordet et al.,1997 ) and besides in drug nuts at postmortem. This D3 receptor, in animate beings, has shown to increase the motive 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 nerve cells because some have this important loss of mesencephalon. Dopamine agonist drugs normally act on D1 and D2 receptors but the nerve cells that normally 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 concluding draftsss2010-04 ( Apr ) 2010-04 ( Apr ) scan0022.jpg ( Taken from Meyer. J.S. and Quenzer, L.F,1997 )

It is besides rather amazing that Pramipexole has a higher affinity for this D3 receptor than other dopamine receptors. These developments are painting a image of the ground why some Palladium patients develop this medicine dependence and behavioral alteration. The function of D3 receptor has non been proven yet and the deduction of dopamine agonist such as Pramipexole has merely been confirmed in little meta-analyses ( Gallagher et al. , 2007 )

D3 receptors were evaluated in carnal theoretical accounts of dependence as a mark for the development of medicine against drug dependence ( Heidbreder et al, 2005 ) but, it was difficult to measure their effectivity in vivo. Eventually, some D3 partial agonists and adversaries were developed, such as SB-277011A ( Le Foll et Al, 2000 ) . It was found to suppress drug seeking behaviors and honoring effects of drugs ( Vorel et al, 2002 ) . If the consequences obtained in carnal theoretical accounts could be replicated in human nuts, the D3 receptor adversaries could potentially supply the way to supply effectual medicine against drug dependence.

Chapter 6: Decision

The grounds back uping the association between dopamine agonist and the development of dependence is rather strong but the neurobiological mechanisms involved are ill understood. Several instance surveies and studies appear to associate the DA drugs to the enigma of dependence, chiefly pathological gaming.

At the Centre of it all is ‘Dopamine ‘ because this is what is losing in PD patients and it is what the DA drugs are trying to reconstruct in the limbic part of the encephalon ( Goldstein, R.Z. et al 2002 ) .

It is possible that the medicine does non merely reconstruct the degrees of Dopastat in the dorsal striatum back to normal, but they may besides over stimulate and bring forth excessively much Dopastat. However, an addition in dopamine alone is unequal to do dependence, hence there must be a combination of structural and neurological alterations.

Pramipexole has been the most prescribed drug to PD patients harmonizing to most instance surveies. This means that it is more likely to be blamed for the alterations seen as it is over-represented. However, most of the prescribed Dopastat agonists have been associated with pathological gaming, hence there is a high opportunity that the consistence of Pramipexole being prescribed correlatives with it being implicated as the perpetrator.

Pramipexole does look to hold a high affinity for the D3 receptor, which is another major factor. This carries the most weight in footings of grounds in support of why some people develop this dependence and others do non. It is shown that some patients suffer frontal lobe wasting, hence exposing more of the D3 receptors in that part of the encephalon where Dopastat acts.

If the patient is prescribed a drug with a high affinity for this receptor, so the likeliness of dependence happening additions. A combination of the drug Pramipexole and the D3 receptor could be the implicit in cause of this deep enigma though the grounds is rather unequal. I believe that the part of the D3 receptor warrants farther attending. There is doubtless a batch left to larn in how the PD patients on DA medicine develop these alterations, farther still to larn about how dopamine agonists affect the encephalon of PD patients.

Management and Future Positions

As it was found that a batch of PD patients were taking a higher than normal dosage of DA drugs, this should clearly be rectified and avoided. Clinicians should be more watchful and cognizant, examining inquiries should be asked of the patient ‘s wonts in order to avoid farther complications. Possibly exchanging between different DA drugs might be good and could diminish the oncoming of dependence symptoms so the encephalon does non acquire excessively used to it. ( Gallagher, D.A et al 2007 )

Persons most at hazard should besides be identified and screened by either questionnaires or via taking relevant information such as drug usage and chancing history. Further survey should besides be carried out to look into if specific populations are more at hazard. ( Dorom Merims and Nir Giladi 2008. )

Self-help group should be created to assist persons who are enduring from such dependence, a group non for the general population but specifically for PD patients.



Glossary of Footings

Basal Ganglia: A series of four neurone bunchs which are responsible for conveying information from intellectual cerebral mantle to the encephalon root and cerebellum, in order to modulate organic structure motor motions.

Dopamine: A monoamine neurotransmitter derived in parts of the encephalon that govern motion and emotions.

Neurotransmitters: Natural nervus chemicals that communicate between neurones by conveying nervus urges from one cell to another.

Receptors: Molecules normally expressed on the cell surface ( there are some intracellular receptors ) , where peculiar courier molecules ( i.e. neurotransmitters ) can adhere in a lock-and- key mechanism.


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