Abstract
Abstract
Neuropsychiatric symptoms are common non-motor symptoms in Parkinson’s disease (PD). Apathy and impulse control disorders (ICD) are two opposite motivational expressions of a continuous behavioural spectrum involving hypo- and hyperdopaminergia. Both syndromes share pathological (decreased vs increased) dopamine receptor stimulation states. Apathy belongs to the spectrum of hypodopaminergic symptoms together with anhedonia, anxiety and depression. Apathy is a key symptom of PD which worsens with disease progression. Animal models, imaging and pharmacological studies concur in pointing out dopaminergic denervation in the aetiology of parkinsonian apathy with a cardinal role of decreased tonic D2/D3 receptor stimulation. ICDs are part of the hyperdopaminergic behavioural spectrum, which also includes punding, and dopamine dysregulation syndrome (DDS), which are all related to non-physiological dopaminergic stimulation induced by antiparkinsonian drugs. According to clinical data tonic D2/D3 receptor stimulation can be sufficient to induce ICDs. Clinical observations in drug addiction and PD as well as data from studies in dopamine depleted rodents provide hints allowing to argue that both pulsatile D1 and D2 receptor stimulation and the severity of dopaminergic denervation are risk factors to develop punding behavior and DDS. Imaging studies have shown that the brain structures involved in drug addiction are also involved in hyperdopaminergic behaviours with increase of bottom-up appetitive drive and decrease in prefrontal top down behavioural control.
Abbreviations
Parkinson’s disease Impulse control disorders Dopamine dysregulation syndrome Dopamine agonists Deep brain stimulation Subthalamic nucleus 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine N-methyl-D-aspartate
The aim of the present review is to provide an overview of available data contributing to a better understanding of the full spectrum of dopamine-dependent behavioural disorders observed in PD.
APATHY AND HYPODOPAMINERGIC BEHAVIOURS
The term apathy was originally described as abehavioural syndrome that refers to a set of simultaneous behavioural, affective and cognitive features variably characterized by reduced interests, emotions and motivations, not attributable to diminished level of consciousness, cognitive impairment, or emotional distress [1]. Apathy can be considered as the clinical translation of lack of motivation. Typically the patient’s subjective complaint is fatigue. Apathy involves a reduction in goal oriented behaviours that can be observed related to three different subdomains: cognitive apathy, that results in the impairment of executive functions that are needed to elaborate an action plan, emotional-affective apathy, that involves the impairment in emotional reactivity and autoactivation apathy that refers to the impairment of the spontaneous initiation of cognitive and emotional processes [2–4].
Apathy is an almost constant symptom of major depression and dementia, it overlaps with anhedonia and is frequently encountered in cortico-subcortical disease of various aetiology such as Alzheimer’s disease, schizophrenia, parkinsonian syndromes or in diffuse periventricular white matter lesions disrupting the ascending monoaminergic and cholinergic pathways [3, 6]. Its prevalence in the elderly population is around 25% [7]. For this review, we will focus on apathy as a symptom of Parkinson's disease (PD) to elucidate its physiopathology. We will analyse mechanisms based on two different models: 1.apathy in de novo PD patients, to study the impact of dopamine, and 2. apathy in the advanced stage of the disease, as a prominent part of dopamine withdrawal syndrome after deep brain stimulation (DBS).
Model of apathy in drug naïve PD patients
Apathy has been considered as a notable symptom of PD since the 19th century [8]. Apathy, altogether with depression and anxiety, is one of the premotor non-motor symptoms of the disease that can antedate the clinical diagnosis by ten years [9]. The role of apathy as a premotor symptom has been nicely documented in the case of Ray Kennedy, the famous English soccer player who reported lack of energy as well as other non-motor symptoms up to fourteen years before the clinical diagnosis of the disease [10].
Nowadays, the general prevalence of apathy in PD ranges from 17% up to 70% according to patient selection, antiparkinsonian treatment, and assessment tools [11].The prevalence of apathy in de novo PD patients ranges between 20–36% , using different evaluation tools [11–14]. In early disease the prevalence of apathy showed a trend for decrease in treated versus drug-naïve patients [14]. In de novo PD, apathy correlated to the severity of motor symptoms and cognitive deterioration. When controlling for these, it was still associated with fatigue and anhedonia [12]. According to Braak staging, de novo PD corresponds to extension of the synucleinopathy to midbrain dopaminergic neurons. In a recent study performed in early PD patients with a two years follow up since the beginning of dopamine therapy (dopamine agonists [DAs] or levodopa), the only non-motor symptoms with a significant reduction in their prevalence were those related to feeling sad, blues and anxiety [15]. This follow-up study showing the improvement of non-motor behavioural symptoms in de novo PD patients after introduction of dopaminergic medication reinforces the idea of dopaminergic aetiology of psycho-behavioural symptoms. In addition, this suggests that the presence of apathy in treated PD patients could be masked due to the therapeutic effect of dopaminergic drugs during the honeymoon period. Once patients start developing motor and non-motor fluctuations, the neuropsychological symptoms appear again during the non-motor off period [16–18].
There is some evidence supporting improvement of apathy using dopamine agonists with a selective affinity for D2-D3 dopamine receptors in early PD. In a randomised placebo controlled study, where most of the patients were already on levodopa, adding rotigotine, a D2-D3 dopamine agonist significantly improved sleep/fatigue and mood/apathy domains of the Non-Motor Symptoms Scale, after one month of treatment [19].
In more advanced stages of PD, the prevalence of apathy increases with occurrence of dementia [14], which may reflect not only degeneration of ascending monoaminergic and cholinergic neurotransmitter systems but also diffuse postsynaptic striatal and cortical synucleinopathy [20]. As for drug resistant akinesia related to non-dopaminergic lesions in advanced stage disease, apathy would then logically be expected to develop progressive resistance to dopaminergictreatment [3].
Model of apathy in advanced stage PD treated by STN DBS allowing for major decrease in dopaminergic treatment
Patients with PD that undergo bilateral deep brain stimulation (DBS) in the subthalamic nucleus (STN) usually are able to decrease dopaminergic medication by about 50% after surgery. Apathy is frequent in PD patients with STN-DBS, especially in the first postoperative months in the context of dopamine withdrawal, but also in the long term with progression of the dysexecutive syndrome [21]. STN-DBS, allowing for massive decrease in dopaminergic treatment because of the improvement in motor symptoms, has been used as a model to study non-motor hypodopaminergic symptoms [22]. In order to unmask non-motor symptoms, experimental drug management exceeding drug decrease as used in clinical routine, included complete arrest of dopamine agonists at surgery in all the patients plus a marked decrease in levodopa up to the level allowed by the motor state improved with STN-DBS. Despite this drastic drug reduction, and although part of the surgical candidates had ICD or DDS, there was no acute dopamine agonist withdrawal reported as is the case in non-surgical patients [23] which can be explained by the stimulating psychotropic effects of STN-DBS that have been shown with acute STN-DBS [24]. Nevertheless, prospective monthly evaluation of apathy over one year showed that half of the patients had developed apathy with a mean delay of 4.7 months and in some individual patients as late as 11 or 12 months after surgery [22]. Apathy occurred very progressively and not in response to changes in stimulation parameters, supporting underlying progressive desensitization of the psychotropic effects of dopaminergic treatment [25] and also partial tolerance to DBS [26], rather than a stimulation effect related to current diffusion to non-motor territories of the STN or outside the STN [27]. PD patients developingpostoperative apathy as well as other hypodopaminergic symptoms, such as depression or anxiety, had more severe non-motor fluctuations at baseline and a more severe and more diffuse mesocorticolimbic dopaminergic denervation. Introduction of a selective D2 and D3 dopamine agonist (piribedil) in a double-blind placebo controlled study showed significant improvement of postoperative apathy. Interestingly also anxiety and depression showed a clear trend to improvement under piribedil. This confirms a former open study using the D2-D3 agonist ropinirole [28] and provides the proof that postoperative apathy is indeed related to withdrawal of drugs and not to a specific side effect of DBS [29]. In the same study preoperative non-motor fluctuations were improved in parallel to motor fluctuations. Moreover, preoperative hyperdopaminergic behaviours gradually disappeared after surgery. There has been a debate whether ICDs are induced or relieved in patients treated by STN DBS. Some studies showed that ICDs may persist, worsen or develop for the first time after DBS surgery, where as other studies reported an improvement [30]. All these data come from retrospective, non-consecutive series of patients, selected from several centers without systematic evaluation of behavior. Predictors of poor behavioral outcome (i.e. persistence, worsening or new onset of ICDs) were 1) lack of recognition of behaviors pre-operatively, 2) poor or moderate motor outcome, meaning surgical failure, not allowing for drug reduction and 3) a major difference in drug management with high post-operative total levodopa-equivalent daily dosage (2662±1319 mg/day) in patients with ICDs, compared to low dosage (329±363 mg/day) in patients without ICDs. In addition to the paper by Lhommée et al. (2012) a second prospective evaluation of a large consecutive series of patients who had bilateral STN-DBS showed improvement in dopamine addiction (diagnosed by a psychiatrist familiar with substance abuse, based on gold standard diagnostic criteria) and virtual disappearance of several ICDs (pathological gambling, pathological shopping, hypersexuality), with the single exception of binge eating. This notable exception raises the question whether STN-DBS per se might contribute to a rather systematic postoperative weight gain, in addition to other potential explanations for weight increase such as recovery of preoperative weight loss, reduction in caloric consumption related to decrease in rigidity and dyskinesia, decrease in preoperative behavioral hyperactivity and recovery of sleep. Interestingly, in animal models, STN-DBS has been shown to reduce motivation to seek and take cocaine [31], while it increased motivation and perseverative behaviors for obtaining sucrose, a palatable, caloric food highly attractive for the rat [31, 32]. The privileged anatomical relationship between the STN and the lateral hypothalamus [33] might account for such effects, suggesting a separate, differential processing of food-related and other appetitive behaviours by the STN.
Finally a desensitization of the preoperative psychotropic effects of dopaminergic medication has been shown one year after surgery [25]. The postoperative decrease in the severity of hyperdopaminergic behavioural complications thus seems to have the same underlying mechanisms than the decrease in severity of dyskinesia, the motor complication of dopaminergic treatment, with severity of dopaminergic denervation and pulsatile dopaminergic stimulation as their main risk factors [34].
Apathy is commonly seen in the context of depression and anxiety. The three of them have overlapping symptoms. In a recent work by Vriend et al., the authors support the idea of depression and ICDs as different sides of the dopaminergic spectrum. Evidence of depression improvement with D3 agonists and more severe dopaminergic deficits in neuroimaging studies in depressed PD patients compared to non-depressed has been shown [35]. According to this work depression is part of the hypodopaminergic spectrum of symptoms altogether with apathy and anxiety.
Overall these studies seem to validate the concept of opposing hypo- to hyperdopaminergic behaviours and the need for systematic screening for and quantification of non-motor fluctuations in behavioural evaluation of PD [26, 36–38].
Recent lesion-based experimental studies also support the hypothesis of a dopaminergic etiology for apathy and affective-related symptoms in PD. Indeed, systemic administration of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys [39], or partial bilateral lesions of the dopaminergic nigrostriatal system with 6-hydroxydopamine (6-OHDA) in rats [40, 41], led to profound amotivational states uncoupled from motor impairments. These motivational deficits in 6-OHDA lesioned animals were also associated with depression- and anxiety-like behaviours [40, 42], in accordance with a growing body of data showing similar affective impairments in other experimental rodent PD models targeting the dopaminergic system ([43–47]). These behavioural deficits were responsive to dopaminergic medications and particularly to D2/D3R agonists, such as ropinirole and pramipexole [40, 41]. Moreover, motivational deficits in 6-OHDA lesioned rats progressively reappeared after discontinuation of the pramipexole treatment [41], thereby mimicking the reemergence of apathetic symptoms when dopaminergic medications are reduced or withdrawn in PD patients. In another set of experiments, comparing highly selective D1, D2 and D3 receptor agonists the reversion of the motivational deficits induced by the partial dopaminergic nigrostriatal lesions were specifically mediated by D3 but not D2 receptor stimulation [42]. Taken together, these data point toward a strong implication of the dopaminergic denervation in the pathophysiology of apathy and associated affective symptoms in PD. It remains unclear however from these studies, whether apathy would intrinsically result from the loss of dopamine in the nigrostriatal system or the diffusion of the lesion toward more limbic areas [39, 40].
From an imaging point of view, there have been few studies investigating apathetic behaviour. All these studies claim a dysfunction of dopaminergic neurotransmission in the mesocorticolimbic system. In particular, PET investigations with D2/D3 receptor antagonist, i.e. [11C]-raclopride, reported increased binding potential, suggesting a more severe dopaminergic denervation, in apathetic PD patients not only in the striatum, but also in the cingulate and orbitofrontal region, amygdala and dorsolateral prefrontal cortex [28]. More importantly in those mesocorticolimbic regions, there was a reduced endogenous dopamine release as indexed by a weaker reduction in (11C)-raclopride binding following methylphenidate administration. Other imaging studies pointed out as well a severe presynaptic dopaminergic abnormality in the ventral striatum correlated with apathy severity [48]. These dopaminergic abnormalities are paralleled by changes in metabolic activity in the striatum as well as changes in different cortical regions such as cingulate cortex, orbitofrontal, inferior-middle frontal region and temporoparietal cortex in other 18FDG-PET studies [27, 50].
ICD AND HYPERDOPAMINERGIC BEHAVIOURAL DISORDERS
Hyperdopaminergic behavioural disorders are a heterogeneous group of iatrogenic complications induced by dopamine replacement therapy in PD patients[51].
The spectrum of hyperdopaminergic behaviours includes ICD or behavioural addictions in a larger sense [52], DDS and punding [53]. All of them have overlapping symptoms and share common underlying mechanisms [54].
ICDs are a group of disorders characterized by failu-re to resist an impulse, drive or temptation to perform acts that can be harmful to the person itself or to others [51, 55]. The main subtypes of reported ICDs include pathological gambling, hypersexuality, compulsive eating, and shopping [56–58]. The prevalence of ICDs disorders is often underestimated and it ranges from 6 to 18.4% in Western studies [51]. Risk factors for developing ICDs are male gender, younger age at PD motor symptoms onset and longer duration of treatment with DAs [58]. Although not exactly known, enhanced ventral striatal dopamine release due to hypersensitisation of ventral striatal circuit is thought to play an important role in ICDs physiopathology [59]. Complex interactions between DAs (mainly D3 and D2), and dopamine receptor subtypes lead to development of ICDs [60]. D3 receptor is known to be localized to the mesolimbic system and involved with reward and motivated behaviours. PD patients on DAs therapy are more prone to develop ICDs than those who do not use DAs [57] and some authors point that the effect of DAs on ICDs is dose-dependent [61], but longitudinal studies to verify this hypothesis are lacking. Pramipexole, ropirinole, rotigotine, piribedil, and virtually all non-ergot derived dopamine agonist that are being used today in the treatment of PD, with the notable exception of apomorphine, have a relatively selective binding affinity for the D2-family of receptors, which includes the D3 receptor mainly expressed in the limbic system. Levodopa is metabolized to endogenous dopamine with an affinity to both D1 and D2 receptor families. Levodopa is also related to ICDs with potential sensitizing or synergist effects with dopamine agonists [62]. On average, PD patients with ICDs present more severe cognitive impairment, particularly in executive functions, than those without them [63, 64] Severity of executive dysfunction indicates progression of the disease with both the severity of dopaminergic denervation and distribution of alpha-synucleinopathy and typically also duration and dosage of exposure to dopaminergic medications. While executive dysfunction may favour development of behavioural disorders, it is by no means a prerequisite to develop ICD.
DDS is characterized by the presence of discomfort related to non-motor symptoms such as pain or anxiety during “off” periods, and the severity of non-motor off symptoms is at the basis for induction of self-medication, increasing of dosage and development of dopamine dysregulation with an addiction of dopaminergic drugs in excess of those required to control motor symptoms ([65, 66]). Prevalence of DDS in the general population of PD patients is around3-4% [67]. Levodopa and subcutaneous apomorphine injections are considered the most potent trigger of DDS due to their rapid onset of motor and psychotropic stimulant effects and short duration of action [68]. DDS has also been related to dopamine withdrawal syndrome [69]. Risk factors for DDS are novelty-seeking personality, higher alcohol intake and younger PD onset [66]. The disruption of the reciprocal loops between the striatum and structures in the prefrontal cortex following dopamine depletion is thought to predispose to DDS [68]. Regarding neuroimaging studies, evidence of maladaptation and sensitization occurring in DDS has been noted as enhanced levodopa-induced ventral striatal dopamine release when comparing PD patients with DDS to those who do not compulsively take dopaminergic drugs [66].
Punding has been defined as an idiosyncratic stereotyped behaviour characterized by an intense fascination with complex, excessive, non-goal orientated, and repetitive activities [70]. First described in amphetamine and cocaine addicts [71, 72] it has more recently also been reported in PD patients on dopaminergic treatment [73]. The prevalence of punding in PD ranges from 1.4% up to 14% [74]. Risk factors for punding in clinical studies are male gender, younger age, pulsatility and duration of the treatment [70]. Punding frequently leads to serious social disruption due to a specific activity that can occupy a large proportion of the wake time, and patients may become so deeply involved that they forget to eat or take their medications; the behaviours also may extend through the night, causing sleep deprivation [18, 74]. Punding activities are typically related to the patient’s previous occupation or interests. Punding is not driven by obsessions- as in obsessive-compulsive disorders- to relieve a sense of internal tension or fear. The patients are rather attracted bytheir specific punding activity although they are aware of its futility and recognize their behaviours as being disruptive. Nevertheless, they cannot resist the urge to perform themand dysphoria can result if punding behaviour is forcibly interrupted. In general, punders take higher than average doses of levodopa, they have more dyskinesia and they are more likely to use dopaminergic drugs compulsively [70, 76].
While for ICDs the main targets are D3 and D2 receptors, punding is triggered by the pulsatile stimulation of D1 and D2 receptors. In vulnerable PD patients there is an increase in the synaptic activity of the striatum related to tonic and phasic dopamine release on cortical connections within the direct and indirect pathways of the basal ganglia. In these susceptible patients the therapeutic use of dopaminergic drugs leads to an augmented phasic D1 stimulation that strongly increases the activation of appetitive drive areas. On the other hand, D2 stimulation is also increased to a point of overdose situation, due to a supernormal tonic stimulation of this receptor subtype, leading to a hampered engagement of inhibitory cortical areas and reinforcing even more the influence of appetitive drive areas. Moreover, this dopaminergic disequilibrium will lead to recurrent failures in inhibiting dorsostriatal-dependent habitual behaviours [77, 78]. Summarizing, there is a simultaneous overactivation of appetitive drive and a loss of executive control over a rigid habit system, converging into behavioural disinhibition of relatively restricted habi-tual behavioural programs. Levodopa and apomorphine are the molecules that are the most pulsatile and that act through both D1 and D2 receptor subtypes [79]. In fact some works have shown that punders are more likely to use levodopa and subcutaneous apomorphine injections than non punders [70]. Other indirect data supporting this hypothesis is the higher prevalence of punding in England (14% ) than in Canada (1,4% ) while in England apomorphine is available for therapeutic use in PD, in Canada it is not [70].
These distinct behavioural effects of preferential D1/D2 or D2/D3 stimulation might be a critical aspect to capture the differential psychobiological mecha-nisms underlying ICDs and punding respectively. Indeed, D3 receptors are mainly expressed in limbic areas, with a very high level of expression in the ventral striatum (including the nucleus accumbens), compared to its dorsal part [80]. Interestingly, DA is known to mediate goal-directed behaviours within the mesoaccumbal system and to promote habit formation within the nigrostriatal system, especially in its more dorsolateral part [77, 78]. For instance, disruption of DA signalling in the nucleus accumbens blocks the invigorating effects of amphetamine on exploratory and goal-directed behaviours [81, 82], while similar manipulations in the dorsal striatum prevent the formation of stimulus-response learning and abolish the intense stereotyped behaviours induced by amphetamine [82]. Therefore, one may argue that pharmacological agents acting on D2/D3 receptors should predominantly overstimulate the mesoaccumbal DA system, leading to loss of control over appetitive, goal-directed behaviors and hence, ICDs. Conversely, targeting mainly D1/D2 receptorsmay favor the activation of the nigrostriatal DA system, thereby releasing the expression of habi-tual, stereotyped behaviours, as observed in punding.
Although subjects without neurodegeneration of their presynaptic dopaminergic system can also develop punding and DDS on pulsatile dopaminergic stimulation, as seen in cocaine and amphetamine addicts, damage of central dopaminergic pathways seems to be an important risk factor to develop this phenomenon. Indeed, rats with bilateral dopaminergic nigrostriatal lesions induced by viral alpha-synuclein overexpression, but not non-lesioned control animals, exhibit conditioned place preference to a moderate regimen of levodopa administration (12 mg/kg, only four i.p. injection, once every other days) [83]. This suggests that a dopaminergic denervation facilitates the sensitization of behavioral responses to dopaminergic medications, as levodopa exhibited psychostimulant-like properties in the lesioned rats only. In another study carried out in mice, one group received sham injections and the other group intraperitoneal injections of MPTP. Two weeks later, the animals recovered from akinesia (but not dopaminergic denervation) and were treated with extremely high doses of levodopa/carbidopa (200/25 mg/kg) injected i.p. in a pulsatile way twice a day over several consecutive days. Only the previously MPTP-treated animals with a dopamine depletion, but not the sham-injected group, developed stereotypical repetitive behaviours evoking punding within as little as two to three days [84]. Hyperactivity lasted 1.5 to 3 hours after levodopa injection, and this time course was similar to the expected half-life of levodopa and to the duration of peak-dose dyskinesias [85] seen in levodopa-treated PD patients [86]. Furthermore this model also showed that hyperactivity increases over time while keeping the same daily dose of levodopa, suggesting that punding, or sensitization of a specific selected behavioural program, is related not only to the unitarity dosage, but also to the duration of levodopa exposure.
Taking altogether, ICDs seem closely related to other “on” phenomena in PD, the dyskinesias attributed to sensitization in the motor loop. Both “on” symptoms are due to dopaminergic overstimulation through the oscillatory activity in the same frequency band, but with different peaks expressed in different functional areas of the subthalamic nucleus(dorsal area for dyskinesias versus ventral area for ICDs) corresponding to different cortico-subcortical circuits [87]. A recent work suggested that dyskinesias are more related to disease progression and to higher doses of levodopa than to duration of levodopa therapy [88]. The development of dyskinesias and psychomotor hyperactivity with disease progression often leads to weight loss reinforcing even more the pulsatile delivery of treatment and consecutive dopaminergic over-sensitisation. Thus, in this context, the risk of ICDs can increase, despite remaining on a stable daily levodopa dose. Some studies have found a correlation between the severity of punding, ICDs anddyskinesias [76].
Evidence linking ICDs and dyskinesias comes from the observation that both types of hyperdopaminergic phenomena improve with amantadine [53, 90]. For the non-motor “on” state of ICDs, amantadine improved severe pathological gambling in a double blind study performed in 17 patients [91]. In these patients the previous reduction or withdrawal of DAs was not successful to suppress the ICDs. On the other hand, in a large cohort of PD patients there had been a positive correlation with amantadine and ICD [92]. However, as pointed before, amantadine is prescribed to improve dyskinesias which may explain this correlation with amantadine and ICD as both behavioural disorders and dyskinesia tend to occur together if patients are on pulsatile treatment with levodopa, using doses that are too large for the individual patient or if the total daily dopaminergic treatment consisting of levodopa and dopamine agonist are too high for the individual patient and this means that those patients treated with amantadine were likely to be on high doses of dopaminergic treatment and/or on a too pulsatile dopaminergic treatment and that high dopaminergic medication and not amantadine on its own could be responsible of ICDs in this study. Punding, which shares some of the mechanisms of ICD has also been reported to improve with amantadine in a well-documented single case report [89].Amantadine blocks N-methyl-D-aspartate (NMDA) receptors, that are playing a critical role for the development of the abnormal synaptic plasticity in the mesostriatal systems associated with behavioural sensitization and addiction processes [93–95]. Glutamatergic projections from the cerebral cortex modulate signal transduction of basal ganglia-thalamo-cortical circuits and it is thought that sensitized glutamate NMDA receptors also may be required to express levodopa-induced dyskinesias and stereotypies in addition to sensitization of dopaminergic receptors.
There are a number of neuroimaging studies investigating pathologically disinhibited behaviour in the context of ICD and other hyper-dopaminergic states. These functional imaging studies revealed specific differences in the fronto-striatal network. For example, using [11C] raclopride PET to investigate D2 receptor availability in PD patients with ICDs, there was evidence of increased release of dopamine in the ventral striatum but also reduced dopamine release in the midbrain, where D2/D3 receptors are dominated by autoreceptors, the aim of which is precisely to control dopamine release [96–98]. Here again, the link between dyskinesias and ICDs is present. Indeed the severity of dyskinesias and of ICD, notably pathological gambling, is highly correlated with the importance of dopamine release [99, 100]. However this has never been specifically assessed for punding or DDS. Prefrontal mechanisms play also an important role in these ICD. Activation PET studies have shown that DA agonists may decrease activity in medial prefrontal are associated with impulse control [101] and subsequent investigations using the extra-striatal DA receptor ligand [11C]FLB-457 described abnormalities in D2 receptor binding in the orbitofrontal cortex and anterior cingulate cortex in PD patients with impulse controls [98]. However the most intriguing phenomenon giving further arguments in favor of a community of mechanism between apathy and ICDs is that PD patients presenting ICD or at risk to develop ICD have lower dopamine transporter availability in the striatum (dorsal but also ventral) compared to patients without ICD symptoms [102–104]. This may signify a decreased uptake and clearance of dopamine from the synaptic cleft, which can, in turn, induce a hyperdopaminergic state. However other explanations cannot be ruled out such as a compensatory hypersensitivity of post-synaptic dopamine receptors. We cannot as well exclude the fact that these patients could present a greater dopaminergic denervation, which, in turn could induce an overconsumption of dopaminergic drugs leading to ICDs. Interestingly such greater dopaminergic denervation has been shown to be a major factor of the occurrence of apathy when dopaminergic drugs are reduced after STN DBS [103]. Thus, in the future it would of great interest to follow up closely PD patients with different level of DAT level at baseline and see whether those who will develop ICDs are the same as those presenting apathy at baseline or at risk of developing apathy after STN-DBS and are the ones with greater dopaminergic denervation especially in the ventral striatum.
CONCLUSIONS
Apathy and ICDs in PD are the most frequent behavioural expression of the opposite behavioural spectrums of hypo- and hyperdopaminergic behaviours that share pathologic (decreased vs increased) dopamine receptor stimulation states, as also supported by other recent works [105, 106]. On the hyperdopaminergic side of behaviours, there are strong arguments that in punding and DDS dopamine depletion may increase the risk to develop these hyperdopaminergic behavioural disorders, while ICD may develop with D2/D3-receptor stimulation even in the absence of dopaminergic denervation as in patients treated by DA in restless leg syndrome [107]. Data from clinical evaluation in PD, from imaging and from rat model of selective dopaminergic lesions concur and allow some strong conclusions.
Apathy is a complex and key symptom of PD, characterized by diffuse mesostriatal and mesocorticolimbic dopaminergic denervation that increases with disease progression. Although already described in PD in the 19th century, it has been neglected in the levodopa era, as apathy is often masked by dopaminergic treatment prescribed for motor symptoms. It is indeed a levodopa-responsive symptom, at least in early stages of disease, even though apathy in severe dysexecutive dysfunction associated with additional postsynaptic lesions is not accessible to dopaminergic treatment anymore. Given the importance of D3 receptor stimulation to improve apathy, the existing D2/D3 receptor agonists can be used specifically to treat parkinsonian apathy with a lower risk of inducing dyskinesia compared to levodopa and this knowledge can influence the strategy when selecting drug treatment in a particular patient. Severe akinesia as the primary target symptom would be addressed by levodopa rather than dopamine agonists and prominent apathy with little handicap from akinesia would be the ideal indication for a dopamine agonist. Apathy is the most prominent of a series of symptoms such as depression, anxiety, pain, that constitute the hypodopaminergic syndrome.
Hyperdopaminergic behavioural disorders include ICDs, DDS and punding. The different hyperdopaminergic behavioural disorders share overlapping features, but there are some differences in the behavioural aspects and the underlying mechanisms. Punding results from excessive and pulsatile dopaminergic stimulation. Progressive dopaminergic denervation in PD increases the pulsatility of identical drug dosage due to the lack of dopamine storage capacity. Punding, can be considered as being mainly a dysfunction from top-down selection of particular habits (or from top down control) in response to a cue, like cue-induced craving in substance addiction. The same is probably also the case for DDS, where dopaminergic denervation with non-motor off-periods and pulsatile dopaminergic stimulation are the triggers that lead to the vicious spiral of dopaminergic dysregulation. On the contrary to punding and DDS, ICDs seems to be more driven by altered sensitized bottom-up impulsive system with excessive D3 receptor stimulation as the primary driving force. However, there is also a lot of overlap and ICDs (including behavioural addictions not defined as ICD in the DSM V), punding and DDS have been more pragmatically listed together and they can all be considered as hyperdopaminergic behaviours from both a conceptual and treatment perspective[25, 52].
ACKNOWLEDGMENTS INCLUDING SOURCES OF SUPPORT
All authors acknowledge their respective institutional support.
CONFLICT OF INTEREST
The authors declare having no specific conflict of interest in relation to the writing of this review.