Purpose of review
To review the recent advances in the epidemiology and pathophysiology of impulse control disorders (ICD) in Parkinson’s disease (PD).
Large cross-sectional and case-control multicentre studies show that ICDs in PD are common with a frequency of 13.6%. These behaviours are associated with impaired functioning and with depressive, anxiety and obsessive symptoms, novelty seeking and impulsivity. Behavioural subtypes demonstrate differences in novelty seeking and impulsivity suggesting pathophysiological differences. Observational and neurophysiological studies point towards a potential mechanistic overlap between the behavioural (ICDs) and motor (dyskinesias) dopaminergic sequelae. Converging data suggest dopamine agonists in ICDs appear to enhance learning from rewarding outcomes and impulsive choice. ICD patients also have enhanced risk preference and impaired working memory. Neuroimaging data points towards enhanced bottom-up ventral striatal dopamine release to incentive cues, gambling tasks and reward prediction, and possibly inhibition of top-down orbitofrontal influences. Dopamine agonist-related ventral striatal hypoactivity to risk is consistent with impaired risk evaluation.
Recent large scale studies and converging findings are beginning to provide an understanding of mechanisms underlying ICDs in PD which can guide prevention of these behaviours and optimize therapeutic approaches.
Impulse control disorders; Parkinson’s disease; dopamine agonists; pathological gambling; impulsivity
Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait “disinhibition” is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.
dopa decarboxylase; dopamine; disordered gambling; externalizing; impulse control disorders; impulsivity; reward; ventral striatum
Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson’s disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.
PMID: 22766031 CAMSID: cams2373
Parkinson’s disease; Dopamine agonists; Pathological gambling; Impulsivity
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
Impulse control disorders (ICDs), specifically those related to excessive gambling, eating, sex and shopping, have been observed in a subset of people with Parkinson's disease (PD). Although some initial case reports claimed that dopamine replacement therapies, particularly dopamine agonists, cause ICDs, more recent, larger and better controlled studies indicate a more complicated picture. While dopamine replacement therapy use is related to ICDs, other vulnerabilities, some related to PD and/or its treatment directly and others seemingly unrelated to PD, have also been associated with ICDs in PD. This suggests a complex etiology with multiple contributing factors. As ICDs occur in a sizable minority of PD patients and can be associated with significant distress and impairment, further investigation is needed to identify factors that can predict who may be more likely to develop ICDs. Clinical implications are discussed and topics for future research are offered.
Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D2/D3 receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D2/D3 receptor availability in PG, and its association with trait impulsivity. Males with PG (n = 9) and male healthy controls (n = 9) underwent [11C]-raclopride positron emission tomography imaging and completed the UPPS-P impulsivity scale. There was no significant difference between groups in striatal dopamine D2/D3 receptor availability, in contrast to previous reports in drug addiction. However, mood-related impulsivity (‘Urgency’) was negatively correlated with [11C]-raclopride binding potentials in the PG group. The absence of a group difference in striatal dopamine binding implies a distinction between behavioural addictions and drug addictions. Nevertheless, our data indicate heterogeneity in dopamine receptor availability in disordered gambling, such that individuals with high mood-related impulsivity may show differential benefits from dopamine-based medications.
► Assessed 11C-raclopride binding in pathological gambling, a putative behavioral addiction. ► No group difference in striatal dopamine binding from healthy controls. ► Dopamine binding negatively correlated with mood-related impulsivity (‘Urgency’).
Gambling; Impulsivity; Dopamine; Neuroimaging; Addiction; Striatum
Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's Disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly Dopamine Agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n=22) and without (n=19) active ICD symptoms. Patients performed the task both ‘on’ and ‘off’ DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their ability to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients.
Impulse Control Disorders; Dopamine Agonists; Parkinson Disease; Risk behavior
In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.
Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the “brain reward cascade,” especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD2 A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other “reward genes” are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.
attention deficit hyperactivity disorder (ADHD); genes; reward dependence; reward deficiency syndrome; treatment; neuropsychological deficits
The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.
Alpha-synuclein; impulse control disorders; impulsivity; Parkinson's disease
Dopaminergic medication for motor symptoms in Parkinson’s disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.
Parkinson’s disease; pathological gambling; impulse control disorders; decision-making; dopamine
Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease.
There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, can occur as a complication of Parkinson’s disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reporting and prospective studies have reported an association between ICDs and the use of dopamine agonists (DAs), particularly at greater dosages, whereas dopamine dysregulation syndrome has been associated with greater dosages of levodopa or short-acting DAs. Data suggest that risk factors for an ICD may include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, personal or family history of substance abuse or bipolar disorder, and a personality style characterized by impulsiveness. Although psychiatric medications are used clinically in the treatment of ICDs, there is no empiric evidence supporting their use in PD. Therefore, management for clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly DAs, and there is emerging evidence that such management is associated with an overall improvement in ICD symptomatology. It is important that PD patients be aware that DA use may lead to the development of an ICD, and that clinicians monitor patients as part of routine clinical care. As empirically validated treatments for ICDs are emerging, it will be important to examine their efficacy and tolerability in individuals with cooccurring PD and ICDs.
Impulse control disorders are a psychiatric condition characterized by the failure to resist an impulsive act or behavior that may be harmful to self or others. In movement disorders, impulse control disorders are associated with dopaminergic treatment, notably dopamine agonists (DAs). Impulse control disorders have been studied extensively in Parkinson’s disease, but are also recognized in restless leg syndrome and atypical Parkinsonian syndromes. Epidemiological studies suggest younger age, male sex, greater novelty seeking, impulsivity, depression and premorbid impulse control disorders as the most consistent risk factors. Such patients may warrant special monitoring after starting treatment with a DA. Various individual screening tools are available for people without Parkinson’s disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease has been developed specifically for Parkinson’s disease. The best treatment for impulse control disorders is prevention. However, after the development of impulse control disorders, the mainstay intervention is to reduce or discontinue the offending anti-Parkinsonian medication. In refractory cases, other pharmacological interventions are available, including neuroleptics, antiepileptics, amantadine, antiandrogens, lithium and opioid antagonists. Unfortunately, their use is only supported by case reports, small case series or open-label clinical studies. Prospective, controlled studies are warranted. Ongoing investigations include naltrexone and nicotine.
Impulse control disorders; Parkinson’s disease; restless leg syndrome; parkinsonism; dopamine agonist; non-motor complication; neurobehavioural
Given that impulse control disorders (ICDs) have been identified among a considerable minority of Parkinson's disease (PD) patients, these conditions have gained increased clinical and research attention in the past decade. Dopamine-replacement therapies, taken to ameliorate PD symptoms, have been associated with ICDs in PD. Unfortunately, there are relatively sparse empirical data regarding how best to address ICDs in PD patients. Conversely, progress has been made in understanding the clinical, neurobiological and cognitive correlates of ICDs in PD. Some of these findings may inform possible courses of action for care providers working with PD patients with ICDs. The literature on ICDs in non-PD populations may also be informative in this regard. The goals of the present article are to outline important clinical characteristics of ICDs in PD, briefly review relevant neurocognitive and neurobiological studies and discuss possible ways to prevent and manage ICDs in PD.
Dopaminergic medication-related Impulse Control Disorders (ICDs) such as pathological gambling and compulsive shopping have been reported in Parkinson disease (PD).
We hypothesized that dopamine agonists (DAs) would be associated with greater impulsive choice, or greater discounting of delayed rewards, in PD patients with ICDs (PDI).
Fourteen PDI patients, 14 PD controls without ICDs and 16 medication-free matched normal controls were tested on (i) the Experiential Discounting Task (EDT), a feedback-based intertemporal choice task, (ii) spatial working memory and (iii) attentional set shifting. The EDT was used to assess impulsivity choice (hyperbolic K-value), reaction time (RT) and decision conflict RT (the RT difference between high conflict and low conflict choices). PDI patients and PD controls were tested on and off DA.
On the EDT, there was a group by medication interaction effect [F(1,26)=5.62; p=0.03] with pairwise analyses demonstrating that DA status was associated with increased impulsive choice in PDI patients (p=0.02) but not in PD controls (p=0.37). PDI patients also had faster RT compared to PD controls F(1,26)=7.51 p=0.01]. DA status was associated with shorter RT [F(3,24)=8.39, p=0.001] and decision conflict RT [F(1,26)=6.16, p=0.02] in PDI patients but not in PD controls. There were no correlations between different measures of impulsivity. PDI patients on DA had greater spatial working memory impairments compared to PD controls on DA (t=2.13, df=26, p=0.04).
Greater impulsive choice, faster RT, faster decision conflict RT and executive dysfunction may contribute to ICDs in PD.
dopamine agonist; gambling; impulse control; Parkinson disease; delay discounting
Impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) are important behavioral problems that affect a subpopulation of patients with Parkinson's disease (PD) and typically result in markedly diminished quality of life for patients and their caregivers. We aimed to investigate the effects of subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on ICD/DDS frequency and dopaminergic medication usage.
A retrospective chart review was performed on 159 individuals who underwent unilateral or bilateral PD DBS surgery in either STN or GPi. According to published criteria, pre- and post-operative records were reviewed to categorize patients both pre- and post-operatively as having ICD, DDS, both ICD and DDS, or neither ICD nor DDS. Group differences in patient demographics, clinical presentations, levodopa equivalent dose (LED), and change in diagnosis following unilateral/bilateral by brain target (STN or GPi DBS placement) were examined.
28 patients met diagnostic criteria for ICD or DDS pre- or post-operatively. ICD or DDS classification did not differ by GPi or STN target stimulation. There was no change in DDS diagnosis after unilateral or bilateral stimulation. For ICD, diagnosis resolved in 2 of 7 individuals after unilateral or bilateral DBS. Post-operative development of these syndromes was significant; 17 patients developed ICD diagnoses post-operatively with 2 patients with pre-operative ICD developing DDS post-operatively.
Unilateral or bilateral DBS did not significantly treat DDS or ICD in our sample, even though a few cases of ICD resolved post-operatively. Rather, our study provides preliminary evidence that DDS and ICD diagnoses may emerge following DBS surgery.
To date, while the contribution of the striatum in executive processes is well documented, the role played by striatal dopamine during tasks requiring executive functions is still unknown. We used D2-dopamine receptor ligand [11C] raclopride PET in healthy subjects while performing the Montreal Card Sorting Task (MCST). We observed a striatal reduction in [11C] raclopride binding potential during planning of a set-shift when compared with matching according to an ongoing rule. These findings suggest that striatal dopamine neurotransmission increases significantly during the performance of specific executive processes confirming previous evidence of striatal activation during fMRI studies. The present observation may provide some insights on the origin of cognitive deficits underlying certain neurological disorders associated with dopamine dysfunction, such as Parkinson’s disease.
PMID: 16982202 CAMSID: cams1538
Positron emission tomography; Functional imaging; Raclopride; Dopamine; Basal ganglia; Executive functions; Cognition
Striatal dopamine neurotransmission is critical for normal voluntary movement, affect and cognition. Dysfunctions of its regulation are implicated in a broad range of behaviors and disorders including Parkinson’s disease, schizophrenia and drug abuse. Extracellular dopamine levels result from a dynamic equilibrium between release and reuptake by dopaminergic terminals. Both processes are regulated by multiple mechanisms. Here we review data characterizing how dopamine levels are regulated by presynaptic autoreceptors and heteroreceptors, an area intensively investigated due to advances in real time electrochemical detection of extracellular dopamine, i.e., fast-scan cyclic voltammetry and amperometry, and the development of mutant mouse lines with deletions for specific receptors.
dopamine; release; autoreceptor; heteroreceptor; cyclic voltammetry; striatum
Recent studies have linked dopamine agonist (DA) usage with the development of impulse control disorders (ICDs) in Parkinson’s disease (PD). Little is known about optimal management strategies or the long-term outcomes of affected patients. To report on the clinical interventions and long-term outcomes of PD patients who developed an ICD after DA initiation. Subjects contacted by telephone for a follow-up interview after a mean time period of 29.2 months. They were administered a modified Minnesota Impulse Disorder Interview for compulsive buying, gambling, and sexuality, and also self-rated changes in their ICD symptomatology. Baseline and follow-up dopamine replacement therapy use was recorded and verified by chart review. Of 18 subjects, 15 (83.3%) participated in the follow-up interview. At follow-up, patients were receiving a significantly lower DA levodopa equivalent daily dosage (LEDD) (Z = -3.1, P = 0.002) and a higher daily levodopa dosage (Z = -1.9, P = 0.05), but a similar total LEDD dosage (Z = -0.47, P = 0.64) with no changes in Unified Parkinson’s Disease Rating Scale motor score (Z = -1.3, P = 0.19). As part of ICD management, 12 (80.0%) patients discontinued or significantly decreased DA treatment, all of whom experienced full or partial remission of ICD symptoms by self-report, and 10 (83.3%) of whom no longer met diagnostic criteria for an ICD. For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms.
dopamine agonist; gambling; impulse control disorders; Parkinson’s disease
There exists a remarkable diversity of neurotransmitter compounds in the striatum, a pivotal brain region in the pathology of Parkinson’s disease, a movement disorder characterized by rigidity, tremor and bradykinesia. The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration in this disorder, appears to be the major contributor to these motor problems. However, numerous other neurotransmitter systems in the striatum most likely also play a significant role, including the nicotinic cholinergic system. Indeed, there is an extensive anatomical overlap between dopaminergic and cholinergic neurons, and acetylcholine is well known to modulate striatal dopamine release both in vitro and in vivo. Nicotine, a drug that stimulates nicotinic acetylcholine receptors (nAChRs), influences several functions relevant to Parkinson’s disease. Extensive studies in parkinsonian animals show that nicotine protects against nigrostriatal damage, findings that may explain the well-established decline in Parkinson’s disease incidence with tobacco use. In addition, recent work shows that nicotine reduces L-dopa-induced abnormal involuntary movements, a debilitating complication of L-dopa therapy for Parkinson’s disease. These combined observations suggest that nAChR stimulation may represent a useful treatment strategy for Parkinson’s disease for neuroprotection and symptomatic treatment. Importantly, only selective nAChR subtypes are present in the striatum including the α4β2*, α6β2* and α7 nAChR populations. Treatment with nAChR ligands directed to these subtypes may thus yield optimal therapeutic benefit for Parkinson’s disease, with a minimum of adverse side effects.
L-Dopa-induced dyskinesias; Neuroprotection; Nicotine; Nicotinic; Nigrostriatal; Parkinson’s disease
Striatal D2-type dopamine receptors (D2Rs) are implicated in the pathophysiology of neuropsychiatric disorders, including Parkinson’s disease and schizophrenia. Although these receptors regulate striatal synaptic plasticity, the mechanisms underlying dopaminergic modulation of glutamatergic synapses are unclear. We combined optogenetics, 2-photon microscopy, and glutamate uncaging to examine D2R-dependent modulation of glutamatergic synaptic transmission in mouse striatopallidal neurons. We find that D2R activation reduces corticostriatal glutamate release and attenuates both synaptic- and action potential-evoked Ca influx into dendritic spines by approximately 50%. Modulation of Ca signaling is mediated by a PKA-dependent regulation of Ca entry through NMDA-type glutamate receptors that is inhibited by D2Rs and enhanced by activation of 2A-type adenosine receptors (A2ARs). D2Rs also produce a PKA- and A2AR-independent reduction in Ca influx through R-type voltage-gated Ca channels. These findings reveal that dopamine regulates spine Ca by multiple pathways and that competitive modulation of PKA controls NMDAR-mediated Ca signaling in the striatum.
Deviation of dopamine homeostasis is known to be associated with disorders like drug addiction and Parkinson’s disease. As dopamine function is tightly regulated within the basal ganglia circuitry, cortical perturbation would lead to modulation of dopaminergic activity in the striatum. We proposed and tested if somatosensory activity such as forepaw stimulation could modulate dopaminergic function. Specifically, we tested in rats if electrical forepaw stimulation (EFS) could attenuate dopamine release in the brain if dopamine is excessive, and boost dopamine release if dopamine is deficient. We had previously demonstrated that EFS effectively attenuated excessive DA concentration in the striatum. We now show in this manuscript with fMRI that EFS boosted DA release on two DA deficient conditions: 1. with quinpirole challenge, and 2. partial Parkinsonism model (PD). Quinpirole alone decreased dopamine release and thus the cerebral blood volume (CBV) that was restored by EFS. EFS also succeeded in increasing CBV in the basal-ganglia circuitry of the PD rats, but not in the controls. Context-dependent connectivity analysis showed increased connectivity during the basal state in the PD rats, compared to the controls. This “enhanced” yet abnormal connectivity of PD rats was reduced post-EFS. Our results suggest that EFS resets the deficient DA system by partially increasing DA release, in the meanwhile lessening the need for recruiting extra functional network in the basal ganglia circuitry. This study shows not only the capacity of peripheral stimulation to perturb neurotransmitter function, but also the potential of peripheral stimulation to restore neurotransmitter homeostasis.
Impulsive–compulsive disorders such as pathological gambling, hypersexuality, compulsive eating, and shopping are side effects of the dopaminergic therapy for Parkinson’s disease. With a lower prevalence, these disorders also appear in the general population. Research in the last few years has discovered that these pathological behaviors share features similar to those of substance use disorders (SUD), which has led to the term “behavioral addictions”. As in SUDs, the behaviors are marked by a compulsive drive toward and impaired control over the behavior. Furthermore, animal and medication studies, research in the Parkinson’s disease population, and neuroimaging findings indicate a common neurobiology of addictive behaviors. Changes associated with addictions are mainly seen in the dopaminergic system of a mesocorticolimbic circuit, the so-called reward system. Here we outline neurobiological findings regarding behavioral addictions with a focus on dopaminergic systems, relate them to SUD theories, and try to build a tentative concept integrating genetics, neuroimaging, and behavioral results.
Behavioral addictions; Pathological gambling; Binge eating; Compulsive buying; Hypersexuality; Substance use disorders; Mesocorticolimbic circuit; Reward system; Dopamine; Parkinson; Parkinson’s disease; Neurobiology; Risk factors; Impulse control disorders; Functional anatomy
To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson’s disease (PD).
An unstructured screening interview for ICDs (compulsive gambling, buying, and sexual behavior) followed by a telephone-administered structured interview for screen-positive patients.
Two university-affiliated movement disorders centers.
A convenience sample of 272 patients with idiopathic PD who were screened for psychiatric complications.
Main Outcome Measures
Presence of compulsive gambling, buying, or sexual behavior as assessed by the Minnesota Impulsive Disorders Interview.
Eighteen (6.6%) PD patients met criteria for an ICD at some point during the course of PD, including 11 (4.0%) with an active ICD. Compulsive gambling and compulsive sexual behavior were equally common. In a multivariate model, treatment with a dopamine agonist (P = .01) and a history of ICD symptomatology prior to PD onset (P = .02) predicted current ICD. There were no differences between the dopamine agonists in their association with ICDs (P = .21), and daily doses of dopamine agonists were higher in patients with an ICD than in dopamine agonist-treated patients without an ICD (P < .001).
PD patients treated with a dopamine agonist should be made aware of the risk of developing an ICD and monitored clinically. As dopamine agonists are increasing being used for other indications, future research should assess the dopamine agonist-associated risk for ICDs in other populations.