Why do some patients with Parkinsons also suffer from pathological

gambling behaviour?

Parkinsons disease (PD)(Parkinson 1817) is an idiopathic (meaning no clear

cause) neurodegenerative disorder which affects approximately 7 million
people globally and around 1% of those over 60 year old. It is a progressive
disorder with a primary pathology consisting of cell death in the substantia
nigra in the mid-brain, a region containing dopamine producing neurons which
is strongly connected with other areas of the basal ganglia. The principal
symptoms of the disease are related to movement including bradykinesia
(slowness of movement), tremor, and reduced or absent arm swing and
shuffling gate during walking). Cognitive symptoms are also measurable in the
early stages of the disease, possibly due to degeneration in non-dopaminergic
neurotransmitter systems including the nor-adrenergic system (Sara and
Bouret, 2012), or acetyl choline system (Bohnen and Albin ,2011) although
only a proportion of patients will develop more profound cognitive
impairments known as PD Dementia. Social and emotional affects may also be
present, either due to indirect consequences of movement problems leading
to reduced vocal strength and expression or due to neurodegenerative
changes in regions beyond the basal ganglia.

Most recently it has been apparent that a proportion of People with PD can
also develop social behavioural problems due to the presence of impulse
control disorders (ICDs) (Wientraub et al. 2016). This was originally reported
for increased / problem gambling behaviour (Molina et al. 2000), but it is clear
that other behaviours may be affected such as hobbying, compulsive eating,
shopping and "punding" (obsessive collecting and hoarding). According to one
recent large scale study of approximately 3000 patients in the US and Canada
(the “DOMINION” study), the prevalence rate of ICDs is around 14%.
Interestingly rates of ICDs were seen to be slightly higher in patients who were
receiving dopamine medication compared to those who were not, suggesting
that understanding the effects of dopamine medication may provide a clue to
the origin of ICDs in PD.

Great progress has been made in managing and treating the symptoms of PD
through medication. Drugs with a number of different modes of action can be
used in Parkinsons to up regulate dopamine function and improve motor
functioning. L-Dopa, the pre-cursor molecule for dopamine, is the primary
mode of treatment, given because unlike dopamine itself, L-Dopa can cross the
blood-brain barrier. Monoamine oxidase inhibitors (MAOIs) can be given to
prevent the breakdown of dopamine in the synapse by suppressing the action
of the enzyme that breaks it down following release from pre-synaptic
terminals. Finally, substances that act as dopamine agonists by directly
mimicking the effect of dopamine at post-synaptic membrane receptors can be
given to some patients. Examples of direct dopamine agonists include
Pramiprexole and Ropinirole and it is this type of medication that recent
research has suggested may be particularly implicated in the origin of impulse
control disorders in PD.

In order to understand why dopamine agonists might lead to such behaviour it

is necessary to understand the wider role of dopamine in the brain. Whilst the
substantia nigra / striatum dopamine system may be largely involved in
movement (and cognitive functioning: see various studies by Owen as well as
Cools, 2001 for example), other dopamine pathways appear to play an
important role in reward. The importance of dopamine in reward was first
highlighted by animal studies utilising the intra-cranial electrical self
stimulation technique. Studies originally carried out by Olds and Milner (1960s)
showed that animals would repeatedly press a lever to obtain direct current
stimulation when an electrode was implanted in certain regions, in a way that
suggested that the animals found the electrical stimulation pleasurable or
rewarding. Regions that elicited the self-stimulation phenomenon coincided
with areas containing dopamine producing neurons, or regions which received
substantial input from these regions, including the ventral-tegmental area and
what is known as the meso-limbic and meso-cortical dopamine pathways,
which connect with areas involved in emotion such as the medial and orbito-
frontal cerbral cortex (which were damaged in the famous case of phineus
gage). Dialysis of extra-cellular fluid showed that dopamine levels are
increased in animals engaged in intra-cranial self stimulation. Finally, other
reward motivated behaviours such as eating, drinking and sexual behaiviours
are also found to be increased concurrent with stimulation of dopamine
producing regions in the brain.
Coincidentally, the same surgical techniques developed in these animal studies
contributed to non-drug based treatments for PD involving the implantation of
stimulating electrodes into the Basal Ganglia. Whilst effective at abolishing
motor symptoms of the disease, mania and increased ICDs have been reported
as a side effect in patients that have undergone electrical simulator implants
and continued taking dopaminergic medication. In apparent contradiction, low
mood and generalised apathy has also been reported in patients following
stimulator implants although following accompanying reduction in medication
post-sugery (Thobois et al. 2010).

Recently it has been argued that ICDs and Apathy could be considered as
opposite ends of a dimension of affective disorders (Leroi et al. 2012). Whilst
dopaminergic medication might replace dopamine within the cortico-striatal
dopamine circuit (due to cell death in the substantia nigra), it can produce an
"over-dose" effect on the meso-limbic system, leading to an overactive
reward / reward seeking system. Direct dopamine agonists appear to be
particularly prone to causing such effects. Conversely, following electrical
stimulation treatment, cortico-striatal circuits may be brought back into
balance such that dopamine medication is no longer needed to treat motor
symptoms. However, this potentially leave the meso-limbic system with a
deficit of dopamine leading to low mood and apathy. Neuroimaging studies
which have examined "binding potential" for radioactive dopamine ligands
have confirmed that there is relative loss of dopamine in parts of the meso-
limbic system such as the orbito-frontal cortex and amydala in PD patients with
symptoms of apathy (Thobois).

APATHY ICDs

-- Meso-Limbic Dopamine +
+

Specifically for gambling, studies using fMRI have also shown that
Pramiprexole disrupts reward related responses to reward observed in a wheel
of forture type gambling task in the orbitofrontal cortex explaining why these
medications might lead to pathological gambling behaviour (Van Eimeran et
al).
In summary, pathological gambling can be explained by an "over-dose" effect
of dopamine agonists on the meso-limbic dopamine system in some patients.
Individual variations in the extent to which the meso-limbic dopamine system
is affected by the disease, or whether only the substantia nigra and cortico-
striatal system is affected would explain why not all patients experience such
problems and why others conversely may suffer from negative emotional
symptoms such as apathy and depression.