The concepts of the ‘overdose’ theory, the dopaminergic spectrum, and motor and behavioural side-effects of dopamine are relevant to both pathophysiology and clinical management.
The ‘overdose’ theory postulates that efficient function follows a eu-dopaminergic level, with both higher and lower dopamine levels associated with impaired function and a mid-range level associated with optimal function resulting in a Yerkes-Dodson-type ‘inverted-U’ shape function (22
) (). In PD, ventral striatal dopamine is preserved relative to dorsal striatal activity; thus, dopaminergic treatment titrated to alleviate motor dorsal striatal deficiencies may result in an ‘over-dosing’ in ventral cortico-striatal cognitive and limbic pathways.
Dopamine level, function and behaviour
ICDs have also been postulated to exist on a spectrum of dopaminergic level with hyper-dopaminergic levels resulting in ICDs, compulsive medication use and punding behaviours, and hypo-dopaminergic levels resulting in apathy and depression (). Depression (17/63) and apathy (34/63) were reported after subthalamic deep brain stimulation surgery for PD following marked dopaminergic medication withdrawal (23
). Apathy correlated with mesolimbic dopaminergic denervation. ICDs or compulsive medication use behaviours (21/63) resolved in all patients following the marked decrease in dopaminergic medication. Furthermore, pramipexole has been shown to be an effective treatment for depression in PD in a large multicenter study (24
). The symptoms of apathy and depression could thus be conceptualized as a mesolimbic hypodopaminergic syndrome and ICDs as a hyperdopaminergic syndrome.
A unifying view is that there is a common mechanism of action in the motor and non-motor domains of the corticostriatal circuitry as evidenced by similarities between ICDs and Levodopa-induced dyskinesias (reviewed in (25
)). ICDs in PD are associated with oscillatory theta-alpha (mean 6.71 Hz) ventral subthalamic activity and coherence with non-motor prefrontal regions and are distinct from dyskinesias which are associated with a higher theta-alpha peak (mean 8.38 Hz), dorsal localisation and coherence with motor regions (26
). PD patients with punding (27
) or multiple ICDs (18
) also have more severe dyskinesias relative to PD controls. Taken together, this evidence supports potentially unifying neurophysiological mechanisms linking motor and behavioural side-effects of dopaminergic treatment.
ICDs as a behavioural addiction
ICDs in the general population have epidemiological and phenomenological overlaps with substance addiction, leading to their classification as behavioural addictions (28
). The association between ICDs and dopamine agonist withdrawal syndrome (DAWS) with physical and psychological symptoms unresponsive to levodopa provides evidence to support the association with withdrawal (29
) and likely receptor supersensitivity. Although ICDs in PD are potentially an intriguing model for the study of ICDs in the general population, given the chronic exogenous dopamine stimulation, there may indeed be pathophysiological differences between the two groups.
The effects of chronic DA administration are relevant both pathophysiologically and in the interpretation of studies. Acute DA in rodents dose-dependently decreases dopaminergic firing related to D2 autoreceptor stimulation (30
). In contrast, chronic DA administration normalizes dopaminergic and enhances serotonergic firing presumed related to D2/D3 autoreceptor downregulation and 5HT1A autoreceptor downregulation. These findings suggest that neuronal adaptation differences to chronic DA administration may be relevant to the pathophysiology of ICDs.
PD patients with pathological gambling on DA compared to PD controls have increased ventral striatal dopamine release to a gambling task in an [11
C] raclopride positron emission tomography (PET) study (31
). This finding is consistent with observations that different substances of abuse increase striatal dopamine release. What is not clear is whether this gambling-related increased dopamine release is secondary to its role in reward processing, incentive motivation, risk or ambiguity or hedonic tone; we parse these constructs in the following sections.
Dopamine and reward
Research on addiction has highlighted a role for dopamine in mediating reward-related processing leading to both the initial early substance experimentation and acquisition and the subsequent late stages of craving and compulsive use. Phasic release of ventral striatal dopamine is initially triggered by the unexpected receipt of reward but shifts to the cue predicting reward after associative learning (32
) and along with glutamate, is necessary for the formation of conditioned responses. Converging primate and human functional magnetic resonance imaging (fMRI) studies demonstrate that dopamine responsiveness encodes discrepancies between rewards received and those predicted thus acting as a teaching signal signifying a reward prediction error (32
Dopamine replacement therapy may influence physiological function either by exogenous tonic dopaminergic stimulation or interference with the endogenous, physiological, phasic striatal dopamine release. According to a proposed computational model, phasic dopamine activity after unexpected rewards exert a positive reinforcing effect by stimulating D1 receptors, whereas unexpected punishments lead to negative reinforcement by a phasic decrease in D2 receptor-mediated signalling (33
). Persistent tonic stimulation could therefore simultaneously enhance D1-mediated effects and prevent pauses in D2 signalling, impairing negative feedback learning. This effect of DAs has been shown in new onset PD patients without ICDs: unmedicated patients were impaired at learning from positive outcomes and as a consequence of DA administration, were impaired at learning from negative outcomes (34
). With respect to PD patients with ICDs, DAs have been shown in two studies to enhance learning from gain outcomes but the findings to negative outcomes were contradictory(35
DA in PD patients with either problem gambling or compulsive shopping were shown to enhance the rate of learning from gain-specific outcomes (35
). Using a reinforcement learning computational approach that models reward prediction error activity to assess fMRI blood oxygen level-dependent (BOLD) response and indirectly assess phasic dopaminergic activity, DAs were shown to increase ventral striatal activity to prediction error in ICD, signifying a ‘better-than-expected outcome’ and enhanced reward prediction. These results are most consistent with the early acquisition stage and also relevant to forming learned associations with cues.
Dopamine and incentive salience
The incentive motivation theory hypothesises that dopamine alters nucleus accumbens sensitivity to incentive processing such that motivational value is assigned to cues associated with rewards making them desirable (37
). Using [11
C] raclopride PET imaging, PD patients with mixed ICDs were shown to have a heightened striatal dopamine release to heterogenous reward-related visual cues as compared to either neutral cues or to levodopa challenge (38
). These findings were suggested to support an incentive salience process. Similarly, ventral striatal activation to gambling-related cues was demonstrated in a small fMRI study in PD patients with ICDs (39
). These studies are consistent with studies in cocaine dependence demonstrating greater striatal dopamine release in response to cocaine cues (40
). However, a separate study did not demonstrate differences in motivation as measured using response time to a reward incentive task (41
Dopamine and risk and uncertainty
Pathological behavioural choices are associated with both positive and negative financial, social and occupational outcomes, thus consistent with definitions of risky (with known probabilities) or uncertain (with unknown probabilities) choices. Risk is encoded in the striatum and orbitofrontal cortex (42
). Two studies focusing on risk demonstrate that DA increases risk-taking in PD patients with ICDs (36
). This risk-taking bias appears to be unrelated to loss aversion, and is accompanied by lower ventral striatal, orbitofrontal and anterior cingulate activity (43
). The lower ventral striatal activity is consistent with an fMRI study of PD patients with ICDs using the Balloon Analogue Risk Task that examines uncertainty (44
Dopamine, regulation of behaviour and impulsivity
The aforementioned studies focus on ‘bottom up’ striatal mechanism of reward and incentive. Some evidence for impaired ‘top down’ prefrontal regulation is beginning to emerge. Using H2
O PET, in PD patients with pathological gambling engaged in a probabilistic gambling task, apomorphine challenge was associated with decreased activity in circuits involved in behavioural regulation including the lateral orbitofrontal cortex and rostral cingulate cortex (45
). Similarly, resting state single photon emission tomography (SPECT) study in PD patients with pathological gambling demonstrated decreased functional connectivity between the striatum and anterior cingulate cortex, a region involved in negative feedback and conflict detection (8
). These observations are consistent with lower orbitofrontal and anterior cingulate activity observed in subjects with substance use disorders in the general population.
Impulsivity, defined as a lack of behavioural inhibition, has multiple manifestations, including motor response inhibition, rapid decisions, impulsive action or premature responding, and impulsive choice. Impulsive choice is characterised by a preference for small, immediate, rewards, instead of larger, delayed, rewards and implicates the medial striatum, medial prefrontal and orbitofrontal cortex and subthalamic nucleus (reviewed in (46
)). Several studies have demonstrated enhanced impulsive choice in PD patients with ICDs using delay discounting tasks with hypothetical long delayed monetary rewards (18
) and real-time short delay monetary rewards (47
). In one study, impaired delay discounting with intact reward incentive performance in PD patients with ICDs was interpreted as a potential impairment in waiting for the delayed reward rather than an enhanced incentive towards the immediate reward. Alternatively, impulsive choice demonstrates a magnitude effect, whereby lower impulsive choices accompany increasing reward magnitude. This magnitude effect in delay discounting is less pronounced in PD patients with ICDs suggesting that DA may be associated with greater subjective devaluation of the delayed higher reward magnitude (18
), resulting in greater impulsivity towards the smaller immediate choice.
With respect to other forms of impulsivity, DAs appear to enhance the rapidity of decision-making, also known as reflection impulsivity, in PD patients with ICDs, suggesting that the long term negative consequences may not be as carefully considered (47
). That this form of impulsivity is also impaired by subthalamic stimulation (48
) and that we show an impairment in patients with ICDs may explain impulsive behaviours observed in the postoperative period. Impulsive PD patients do not perform differently to non impulsive PD patients on the Stroop Colour Word test (36
) that probes inhibition of prepotent responses and response selection associated with anterior cingulate function.
The question of whether PD patients with ICDs have lower D2/D3 receptor levels is potentially intriguing given rodent studies suggesting premorbid higher impulsivity and lower D2/D3 receptor levels predicts risk for cocaine addiction (49
). The evidence from cross-sectional [11
C] raclopride studies are mixed and may be limited by methodology. PD patients with pathological gambling have lower D2/D3 receptor binding on medication when performing a control task suggesting either lower D2/D3 receptor levels or enhanced dopamine release (31
). Two other studies in PD patients with mixed ICDs and compulsive medication use did not detect group differences off medication (38
). Prospective studies may be useful to address these issues.
Of interest, DA appears to enhance altruistic punishment in PD patients with ICDs, where violators of social norms are punished when there is a personal cost association with their behaviour (51
Dorsolateral prefrontal cortical function
Studies using the Frontal Assessment Battery have published disparate conclusions (21
); however, the test is a brief screening instrument with limited specificity for dorsal or ventral prefrontal function. Emerging evidence suggests a potential working memory impairment associated with dorsolateral prefrontal function. Visuospatial working memory tested on medication was impaired in medicated PD patients with ICD compared with those without (47
). Similarly, PD patients with ICD both on and off medications have a significantly reduced digit span compared with PD and control groups (36
). These results suggest that dorsolateral cortico-striatal circuitry in PD with ICD might be similarly affected by ‘overdose’ from exogenous dopamine when on medication and possibly from endogenous dopamine when off medication.
Dopamine receptor subtypes
Dopamine D3 receptors are predominantly expressed in the ventral striatum and mediate reward, emotional and cognitive processes. Pramipexole and ropinirole, two widely used non-ergot DAs have greater D2/D3 selectivity relative to D1. That concurrent levodopa use with a DA increases the odds of an ICD (6
) dovetails with a primate study demonstrating that levodopa administration resulted in ectopic induction of dorsal striatal D3 receptors (54
Genetic polymorphisms may also contribute to ICD susceptibility. Evaluation of dopamine and glutamate receptors and serotonin transporter gene polymorphisms identified D3 dopamine receptor p.S9G and GRIN2B c.366C > G as a risk factor for ICDs in PD (14