670 CNS & Neurological Disorders - Drug Targets, 2011, 10, 670-684

Current Options and Future Possibilities for the Treatment of Dyskinesia and Motor Fluctuations in Parkinson’s Disease M.A. Cenci*,1, K.E. Ohlin1 and P. Odin2

1Basal Ganglia Pathophysiology Unit, Dept. Experimental Medical Science, Lund University, BMC F11, 221 84 Lund, Sweden 2Department of Neurology, University Hospital, SE-221 85 Lund, Sweden and Department of Neurology, Central Hospital, D-27574 Bremerhaven, Germany

Abstract: Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson’s disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes. Keywords: Parkinson's disease, motor fluctuations, dyskinesia, motor complications, basal ganglia, glutamate, , rodent, non-human primate.

INTRODUCTION cycle, a pattern referred to as “diphasic dyskinesia”. This form of The (DA) precursor, L-DOPA, is still the most dyskinesia typically manifests as stereotypic or ballistic movements effective symptomatic against the motor symptoms of mixed with dystonia, and it is particularly severe in the legs [14]. Parkinson’s disease (PD) [1, 2], and it is also the least expensive. Motor fluctuations appear as rapid transitions from good motor Furthermore, L-DOPA treatment increases the life expectancy of function (“on” phase) to severe parkinsonian immobility (“off” PD patients [3, 4]. Standard L-DOPA pharmacotherapy consists of phase) [15, 16]. The earliest and most common type of motor tablets for oral administration, which are taken from three to eight fluctuation consists in a decreased duration of the effect of single L- times per day depending on the individual response and disease DOPA doses, termed “wearing-off phenomenon” or ”end-of-dose stage. L-DOPA is rapidly absorbed from the small intestine, deterioration”. This can appear following the administration of although its absorption depends on the rate of gastric emptying, and daily L-DOPA doses, but also in the form of late night or early on the pH and amino acid concentration of the gastric contents [5]. morning “off” periods. In more advanced stages of PD, fluctuations Plasma concentrations usually peak between 1 and 2 hours after an between”on” and ”off” time can become unpredictable [9]. oral dose, and the plasma half-life is between 1 and 3 hours [6, 7]. Unpredictable responses to single L-DOPA doses may partly To reduce the extracerebral conversion of L-DOPA, standard L- depend on pharmacokinetic problems [17]. The development of L- DOPA preparations also contain a peripheral inhibitor of DOPA DOPA-induced motor complications is however attributed to decarboxylases, such as carbidopa or benserazide [8]. dysfunctional plastic changes that occur in the brain [18-22]. The Despite its cost-effectiveness and ease of administration, L- plastic alterations involved are multiple and complex, but they all DOPA pharmacotherapy has some major limitations. A first, seem to converge on two general mechanisms: presynaptic inescapable limitation depends on the fact that the response to L- dysregulation of DA release and clearance and abnormal DOPA changes during the progression of PD. As the disease postsynaptic responses in dopaminoceptive cells [22, 23], striatal becomes more severe, the need for symptomatic treatment becomes neurons in particular [21]. larger. Thus, both the total dosage and the number of L-DOPA Dyskinesia and motor fluctuations are not the only problems doses per day are usually increased a few years after treatment associated with the use of L-DOPA in PD. The stimulation of DA initiation [9]. At this point, many patients start to exhibit abnormal receptors in mesocorticolimbic regions can contribute to psychotic- involuntary movements (dyskinesia) and motor fluctuations. These like symptoms (hallucinations, vivid dreams, paranoia and complications affect approximately 40% of the patients after 4-6 confusion) [24] and to altered behavioural patterns bearing some years of L-DOPA therapy [10], and up to 90% of the patients by 10 resemblance to compulsive drug use [25]. A matter of even greater years of treatment [11, 12]. The most common pattern of L-DOPA- concern is the limited efficacy of L-DOPA against a range of severe induced dyskinesia consists of choreiform movements that are most motor and non-motor deficits that plague patients in an advanced severe at the time when the drug is producing the maximal relief of disease stage [26]. Non-motor problems that are either not parkinsonian motor symptoms, hence the term ”peak-of-dose” or improved or only partly improved by L-DOPA include ”on” dyskinesia [13]. In some patients, involuntary movements are cardiovascular symptoms (in particular, orthostatic hypotension), most prominent at the beginning and the end of the L-DOPA dosing sleep problems, mood alterations, cognitive deficits, gastrointestinal symptoms (e.g. obstipation and dysphagia), urological problems

(urgency, frequency and nocturia), and pain [27]. Finally, L-DOPA *Address correspondence to this author at the Basal Ganglia Pathophysiology is unable to halt the progression of neurodegeneration [24, 28]. Unit, Dept. Experimental Medical Science, Lund University, BMC F11, 221 84 Lund, Sweden; Tel: +46 46 222 14 31; Fax: + 46 46 222 45 46; Despite all these limitations, L-DOPA remains the gold- E-mail: [email protected] standard treatment to alleviate symptoms of PD [1, 24]. There is no realistic prospect that L-DOPA pharmacotherapy will be radically

1871-5273/11 $58.00+.00 © 2011 Bentham Science Publishers Treatment of Dyskinesia and Motor Fluctuations in Parkinson’s Disease CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 671 replaced by newer treatments in the nearest future. There is with or has been found to be associated with however a need to devise improved methods of L-DOPA delivery an increased risk of cardiac valve regurgitation [38-40]. The effect that can minimize the risk of motor complications. Moreover, was attributed to the agonist activity exerted by pergolide and intense research efforts strive to develop non-dopaminergic cabergoline at the 5-hydroxytryptamine 2B (5-HT2B) receptor. treatments that can be added to L-DOPA in order to reduce the Indeed, stimulation of 5-HT2B receptors has mitogenic properties on occurrence of dyskinesia and response fluctuations and/or to cardiac fibromyoblasts, potentially leading to valvular fibroplasia alleviate non-motor symptoms in PD. [41, 42]. Many of the patients with cardiac valve regurgitation do In this article, we review the current clinical management of not, however, suffer from clinical symptoms related to this motor complications with peroral drug treatment and advanced condition, and the relevance of this side effect is still debated [43]. therapies based on continuous dopaminergic stimulation (CDS) or Table 1. Dopamine Agonists Currenty Used in the Treatment deep brain stimulation (DBS). Thereafter, we summarize and of PD discuss the current status of preclinical research aimed at defining non-dopaminergic drug targets for the treatment of dyskinesia and motor fluctuations. Substance Type T1/2 [h] Elimination

CURRENT TREATMENT OPTIONS Apomorphine Non-Ergot 0.5 Current Management of Motor Complications with Peroral Ergot 6 Hepatic Drug Therapy Cabergoline Ergot 65 Hepatic In the early phases of motor complications, modifications of peroral L-DOPA therapy might improve treatment efficacy. These -Dihydroergocriptine Ergot 15 Hepatic modifications include a fragmentation of the daily L-DOPA dosage Ergot 2-3 Hepatic/renal into more frequent and smaller doses, the use of long-acting dopamine agonists, as well as the use of enzyme inhibitors that can Pergolide Ergot 7-16 Hepatic/renal prolong the effect of each L-DOPA dose [29]. Modified release L- Piribedil Non-Ergot 12 Hepatic/renal DOPA preparations, which prolong the plasma half-life and the pharmacodynamic effect of L-DOPA, were originally proposed as Pramipexole Non-Ergot 8-12 Renal an option [30] (NICE guidelines; www.nice.org.uk). The clinical Pramipexole, prolonged release Non-Ergot 8-12 Renal experience gained over the years indicates that modified release preparations are useful to provide symptomatic control over the Ropinirole Non-Ergot 6 Renal night (when given as a late evening dose). However, they do not Ropinirole, prolonged release Non-Ergot 6, delayed release Renal reduce the severity of motor complications in day-time therapy [31]. (patch) Non-Ergot 5-7 Renal A relatively large number of compounds acting as direct DA receptor-agonists have been introduced in the treatment of PD Table 2. Comparison Between Equivalent Antiparkinsonian during the past 35 years. The prototype of these agonists is Doses of L-DOPA and Dopamine Agonists in bromocriptine, an ergot derivative with agonist activity at the D2 Human PD Patients receptor, but additional DA agonists (both ergot and non-ergot derivatives) are available (Tables 1 and 2). These DA agonists differ between each other in terms of pharmacokinetics and side- Equivalence Doses Single Dose effect profile, but have similar DA receptor specificity, acting L-DOPA 100 mg foremost on dopamine D2/D3 receptors. Moreover, they all have a much longer duration of action than L-DOPA. Initial treatment of Apomorphine 3 - 5 mg PD with these agonists has been consistently reported to reduce the incidence of dyskinesia, dystonia and motor fluctuations [32]. Bromocriptine 10 - 15 mg Dopamine agonists have therefore become first-line agents for de Cabergoline 1,5 - 2 mg novo treatment of young PD patients in many countries (see e.g. German National Guidelines for treatment of Parkinson’s disease, -Dihydroergocriptine 20 - 40 mg www.dgn.org). Unfortunately, all DA agonists have inferior symptomatic efficacy compared to L-DOPA. Most patients starting Lisuride 1 mg their PD treatment on DA agonist monotherapy will therefore need Pergolide 1 mg additional treatment with L-DOPA at some point. It is unclear whether the reduced incidence of motor complications associated Pramipexole 0.7 - 1 mg with the use of DA agonists will persist after adding L-DOPA to the Piribedil 60-90 mg treatment, and the results of different investigations are controversial in this regard [33]. Nevertheless, peroral DA agonist Ropinirole 3 - 5 mg treatment can be useful to patients with advanced PD and motor Rotigotine (patch) 4 mg / 24 h fluctuations, because the addition of a DA agonist to L-DOPA L-DOPA dose equivalents: The dose of the respective drug clinically estimated to have reduces the time spent in the “off condition” [34, 35]. a similar effect compared to 100 mg L-DOPA [251]. While entailing a lower incidence of motor complications, the DA agonists are not devoid of untoward effects. The incidence of Based on experimental as well as clinical results, it has been oedema, somnolence, constipation, dizziness, nausea and speculated that DA agonists might have disease- psychiatric side effects (hallucinations, delusions, confusion or modifying/neuroprotective effects. Some trials using imaging impulse-control disorders) is overall larger for these compounds biomarkers of presynaptic DA fiber integrity (i.e. 18F-DOPA-PET compared to L-DOPA [32, 36]. Daytime tiredness occurs in 5-10% and beta-CIT-SPECT) have demonstrated a slower loss of signal in of DA agonist-treated patients, but can occur also under other types patients treated with DA agonists compared to L-DOPA [44, 45]. of dopaminergic therapy. Ergot-derived DA agonists can induce pulmonary or retroperitoneal fibrosis [37]. Moreover, treatment 672 CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 Cenci et al.

The results are, however, much debated and a neuroprotective motor fluctuations [63, 64]. Moreover, it has been proposed that the effect cannot presently be regarded as proven [46]. lower dyskinesiogenic potential of the DA agonists compared to L- In addition to DA receptor agonists, other dopaminergic DOPA depends on their longer duration of action [62, 65]. treatments for PD include inhibitors of enzymes that inactivate DA, i.e. monoamine oxidase B (MAO-B) [47] and catechol-O-methyl- Pronounced dementia Advanced transferase (COMT) [48]. There are two different COMT-inhibitors YES NO presently available, entacapone and tolcapone. Tolcapone has Continue treatments caused hepatotoxicity in a few patients, and its use should therefore oral Severe tremor with NO insufficient effect of medication YES DBS be associated with regular laboratory controls. The COMT- drug therapy inbibitors are administered together with L-DOPA in patients with NO Motor complications motor fluctuations in order to prolong the effects of single drug doses and reduce the time spent in the ”off”-state. It is still unclear Cognitive/psychiatric impairments YES Apomorphine pump whether the early addition of COMT-inhibitors to L-DOPA in or LCIG Biological age >70-75 yrs YES Apomorphine pump patients who do not yet have motor complications can prevent the or LCIG development of motor fluctuations and dyskinesias. The clinical Disabling dyskinesia YES DBS or LCIG studies thus far have not been able to demonstrate such effects [49, YES Apomorphine pump Contraindications for brain surgery 50]. or LCIG Contraindications for abdominal surgery YES DBS or In addition to prolonging the effect of L-DOPA, MAO-B apomorphine pump inhibitors also have mild efficacy as a monotherapy and can delay All advanced treatment options possible - discuss individual risk/benefit of DBS and pump the need for L-DOPA by several months [51]. Interestingly, the MAO-B inhibitor rasagiline can activate neurotrophic factor signalling [52], raising hopes for a disease-modifying action in Fig. (1). Treatment decision flow chart for patients in an advanced stage of human PD patients [53]. In the so called ADAGIO trial, early PD idiopathic Parkinson’s Disease. LCIG, L-DOPA-carbidopa intestinal gel treatment with rasagiline at a dose of 1 mg per day provided (continuous infusion). benefits that were consistent with a possible disease-modifying The first studies describing intravenous delivery of L-DOPA effect [54]. Several studies provide indications of disease- were published in 1975 [66], and were soon followed by several modifying effects also with the MAO-B inhibitor, selegiline. When other reports showing an improvement of motor fluctuations [67]. selegiline was added to L-DOPA, a slower development of In most cases the patients were, however, only treated for a few symptoms, a reduced need for L-DOPA, and a reduced incidence of days. It proved practically difficult to give L-DOPA intravenously dyskinesias were observed in one trial [55]. over longer times. The first experiences with intraduodenal L- The weak non-competitive NMDA receptor antagonist, DOPA infusion were published in 1986 [68], where effects amantadine has a mild to moderate symptomatic antiparkinsonian comparable to intravenous L-DOPA delivery were reported. This effect, both when used as a monotherapy and in combination with was later confirmed in several other studies (reviewed in [69-71]). other PD drugs. In addition, amantadine reduces L-DOPA-induced L-DOPA-Carbidopa Intestinal Gel (LCIG; Duodopa®) is a dyskinesias (LID) and is now mainly prescribed as an combination of L-DOPA (20 mg/ml) and carbidopa (5 mg/ml) antidyskinetic drug [56]. Current investigations aim at establishing constituted in a pseudoplastic gel that is delivered via portable the antidyskinetic efficacy of additional NMDA receptor infusion pumps. Short-term therapy can be achieved using a antagonists. In this regard, , a compound chemically nasoduodenal catheter, but long-term treatment is achieved by related to amantadine [57], appears particularly promising because means of a duodenal catheter. This is inserted by gastroentero- it has the potential to improve both cognitive function [58] and logical intervention (most often a so-called percutaneous dyskinesia in PD [59]. endoscopic gastrostomy, PEG, or, in some cases, jejunostomy). Anticholinergic drugs belong to the oldest class of anti- Controlled studies have shown that changing from peroral L-DOPA Parkinsonian medicines. These might have beneficial effects therapy to LCIG infusion results in a stabilization of both plasma against tremor and dystonia, in particular, but there is little L-DOPA concentrations and clinical status, with a pronounced published evidence to support such effects (NICE Guidelines; reduction of motor fluctuations and time spent in “off”, and an www.nice.uk). Because of their relatively strong tendency to increased time spent in a good “on” state [69]. A blinded produce autonomic side effects and cognitive impairment randomized cross-over study comparing LCIG monotherapy with anticholinergics are normally used as second-tier therapies, and individually optimized peroral therapy has demonstrated an their prescription is limited to patients without cognitive problems. increase in daily “on” time from 81% to 100% and an improvement in health-related quality of life following LCIG infusion [72]. In a Management of Severe Motor Complications by Continuous German study, 13 patients treated with LCIG experienced a mean Dopaminergic Stimulation 82% reduction of time spent in “off” per day, whereas the time spent in “on” without dyskinesia increased from 30% to 90%. Peak- Optimizations of peroral dopaminergic pharmacotherapy are dose L-DOPA-induced dyskinesia virtually disappeared during a usually insufficient to control severe dyskinesias and motor mean follow-up time of 6 months [73]. Similar effects on motor fluctuations. In the advanced complicated phase of PD, three types fluctuations and dyskinesias have been reported in a number of of interventions currently represent the most effective options, i.e. other studies [74-78]. We have verified the antidyskinetic effect of continuous duodenal L-DOPA administration, subcutaneous continuous duodenal L-DOPA infusion in a dedicated study on 9 apomorphine infusion, or deep brain stimulation (Fig. 1). patients changing from peroral therapy to LCIG. The mean Continuous dopaminergic stimulation treatments (CDS) for PD dyskinesia severity (as detected with repeated scoring over 3 days) were developed based on the proposal that a continuous supply of was reduced by 90% over a period of 6 months. Upon drug L-DOPA and/or a continuous occupancy of DA receptors by long- challenge tests performed before and after 6 months of LCIG acting agonists would be required to adequately reproduce the therapy, an identical dose of L-DOPA produced significantly lower physiological features of nigrostriatal DA transmission [60-62]. In dyskinesia scores (-70%) following pump treatment (Odin, addition to the experimental data, in vivo imaging studies in PD unpublished results). The improvement in dyskinesia in spite of patients strongly support the association between rapid and large unchanged (or even increased) daily L-DOPA equivalent doses changes in striatal DA release and the occurrence of dyskinesia and indicates that what causes dyskinesia is not L-DOPA itself, but Treatment of Dyskinesia and Motor Fluctuations in Parkinson’s Disease CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 673 rather the pulsatile nature of DA receptor stimulation resulting from (typically 2-4 mg), and this has to be titrated individually in each peroral L-DOPA treatment [73-75, 77]. patient. The injections are delivered to the patient’s lower abdomen Initially, duodenal LCIG infusion is most commonly given only or outer thigh upon the first signs of an "off" episode. Domperidone during day-time. In patients experiencing night-time problems with is given during the first days of treatment and can later be tapered Parkinson symptoms and suboptimal sleep, a 24-hour treatment can off in most patients. The efficacy of this treatment has been bring significant improvement of sleep without inducing further demonstrated in a number of studies [97, 98]. Injections of side effects or tolerance [79]. A recent investigation on LCIG apomorphine effectively interrupts “off” periods: the mean time in infusion and the non-motor aspects of PD demonstrated “off” states per day is reduced by around 50%, and the remaining pronounced improvements on several non-motor symptoms, “off” periods are less severe than those occurring before the start of including gastrointestinal, urological, cardiovascular and cognitive apomorphine treatment [85]. problems, as well as sleep and pain, when switching from peroral to pump therapy [77]. Compared with motor symptoms, the Transdermal Drug Delivery improvement in non-motor symptoms showed a stronger correlation Transdermal drug delivery is a relatively recent development with the amelioration of health-related quality of life. The adverse tried for several DA agonists with the aim of providing a events of LCIG therapy are mainly related to the infusion method, continuous drug supply. A transdermal patch formulation of the including dislocation or occlusion of the duodenal catheter, leakage non-ergolinic DA receptor agonist, rotigotine is indicated either as a in the infusion system and problems related to the PEG monotherapy in the treatment of early-stage PD or as an adjunct to establishment. L-DOPA across all disease stages. Transdermal rotigotine has been shown to be superior to placebo in patients with early-stage and Apomorphine Treatment advanced PD, although non-inferiority to the oral DA receptor The efficacy of apomorphine in treating Parkinson symptoms agonists, ropinirole or pramipexole, was not consistently was first demonstrated in 1951 [80]. A broader clinical application demonstrated [99, 100]. The patch delivery option is advantageous of apomorphine became possible after discovering that in several situations, such as, (i) when peroral delivery is domperidone (a peripherally acting DA-receptor antagonist) could contraindicated by specific medical conditions (dysphagia; be coadministered with apomorphine to block its peripheral adverse gastrointestinal side effects of peroral drugs; perioperative reactions (nausea, vomiting, orthostatic hypotension) [81]. Since conditions; gastrointestinal dysfunction with delayed gastric the late nineteen-eighties, apomorphine has been in use for PD emptying); (ii) in patients with therapy compliance problems (due treatment, mostly in the form of subcutaneous (s.c.) infusions or to e.g., cognitive difficulties); (iii) in patients with Parkinson- injections [82, 83]. Together with L-DOPA, apomorphine is the related sleep disturbances in late night/early morning. The most pharmacological treatment exerting the strongest effects on PD common side effects of rotigotine are skin reactions, which occur motor symptoms. Following s.c. injection, apomorphine has a half- very frequently and lead to termination of the therapy in about 5% life in distribution phase of about 5 minutes, leading to a clinical of the treated patients [99-101]. Lisuride and apomorphine are also effect after 5-10 minutes. The biological half-life in elimination being investigated regarding the possibility of a transdermal phase is around 33 minutes and the effect duration is about 45 delivery [102, 103]. minutes [84]. Because of its short duration of action, apomorphine is currently administered by continuous subcutaneous infusion via a Current Surgical Management of Motor Complications portable infusion pump. This treatment is best suited for the Functional neurosurgery, including lesional surgery and deep severely disabled patient who has a good L-DOPA response, but brain stimulation (DBS), is now widely indicated as a treatment whose condition is dominated by prolonged or frequent “off” option for PD when conventional pharmacological treatments fail. periods and/or peak-dose dyskinesias despite optimized oral drug Compared to high-frequency DBS, lesional neurosurgery is an treatment [85-87]. In a review of clinical outcomes of continuous irreversible intervention with a larger incidence of complications, apomorphine infusion therapy [88], including 11 published studies and it is therefore scarcely used today. For DBS, macroelectrodes (mainly [84, 87, 89-94]), the treatment resulted in an average 61% are stereotactically implanted in the brain structure of interest and reduction of the time spent in the “off” phase after a mean follow- connected to an electrical stimulator, which is positioned up period of 21 months. The daily L-DOPA dosage could be subcutaneously in the sub-clavicular region. The basic stimulation reduced by about 39%, and dyskinesias were significantly improved parameters (voltage and frequency) can thus be individually [91, 95]. When L-DOPA and apomorphine tests were performed adapted. Currently, two brain nuclei are mostly commonly used as a before and after 6 months of apomorphine infusion, identical doses target for DBS in the complicated stages of PD: the internal of L-DOPA/apomorphine produced 40% less dyskinesias following segment of the globus pallidus (GPi), and the subthalamic nucleus pump treatment [95]. The effects of apomorphine infusions seem to (STN). Stimulation of the STN has become the most widely used be stable over long-term follow-up [96]. The most pronounced method. This intervention has been found to be more effective than clinical improvements using apomorphine infusion are seen in medical treatment in patients with advanced PD and motor patients who manage with this treatment as a monotherapy [88]. fluctuations in a randomized multicenter study with health-related However, in most cases apomorphine needs to be combined with quality of life as the primary outcome parameter [104]. When peroral L-DOPA therapy to achieve a full clinical effect. The most comparing both STN- and GPi-DBS with best pharmacological frequent problem associated with apomorphine infusion is the treatment in patients with advanced PD, DBS was found to be formation of subcutaneous nodules. This occurs in almost all superior using either target [105]. Regarding long-term outcome, a treated patients, and may lead to therapy discontinuation. The slow worsening of hypokinesia has been demonstrated, the effects problem can be partly prevented by avoiding apomorphine against tremor and rigidity being more stable [106]. STN- concentrations higher than 5 mg/ml, and by changing the infusion stimulation is often regarded as having a stronger antiparkinsonian area at least twice per day. The prevalence of psychotic effect than GPi-stimulation, but this has not yet been proven in complications is not higher with apomorphine compared to other comparative clinical studies. dopaminergic therapies. Hemolytic anemia has been reported in Regarding STN-stimulation a meta-analysis has shown an about 3% of the treated patients [90, 93]. improvement in UPDRS motor scores by 50-52% (comparable to Besides pump treatment, apomorphine can also be given as s.c. L-DOPA) and a reduction of L-DOPA doses by 50-60% [107]. A bolus injections in order to terminate “off” periods occurring in reduction of dyskinesias by 54-74% has been demonstrated in spite of an optimized peroral therapy. The effective dose is the controlled studies [104, 105], an effect obtained mainly through lowest apomorphine dose producing a full antiparkinson effect reduction of dopaminergic [108]. Procedure-related 674 CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 Cenci et al. side effects, like intracerebral bleeding, infections and much closer to clinical application than any ex vivo gene transfer misplacement of electrodes (with need for replacement) occur in up approach. In vivo gene transfer consists in supplying DOPA- or to 4% of cases, with an estimated mortality of 0.4% and long-term DA-synthetizing enzymes to DA-denervated brain regions. One morbidity of 1% [109]. Neuropsychological worsening is mainly successful strategy is to make multiple striatal injections of seen with respect to verbal fluency and in the Stroop test (which recombinant adeno-associated virus (rAAV) coding for TH and measures executive functions, such as selective attention, cognitive GCH1, which results in efficient DOPA synthesis that is associated flexibility and processing speed) [110, 111]. Older patients seem to with significant behavioural improvement in 6-OHDA-lesioned have a greater risk of cognitive worsening compared to younger parkinsonian rats [119]. When gene transfer of TH and GCH1 was ones, and the prevalence of cognitive side effects shows a applied to already dyskinetic rats, the severity of L-DOPA-induced pronounced variation across studies. The procedure is associated dyskinesia (provoked by peripheral drug injections) decreased by at with an increased risk of suicide (15-fold larger risk during the first least 80% over a 12 week period [120]. This effect was paralleled postoperative year, with a slow normalization over time [112]). The by reversal of maladaptive molecular changes associated with indications for STN-DBS are, severe disease with motor dyskinesia, such as the upregulation of FosB and opioid precursor fluctuations and/or tremor that cannot be adequately controlled with genes in striatal neurons [120]. A more recent study using pharmacological therapy (Fig. 1). STN stimulation is normally only optimized gene delivery (rAAV serotype 5 vectors instead of rAAV recommended in patients with an age below 70-75 years. Cognitive serotype 2) has shown improved efficacy in terms of sensorimotor decline and major psychiatric symptoms are commonly regarded as recovery and resistance to the induction of L-DOPA-induced- contraindications (Fig. 1), whereas a good response to L-DOPA is a dyskinesia in previously untreated animals [121]. Similar rAAV- prerequisite to this intervention. based in vivo gene transfer approaches have been applied with High-frequency stimulation of the GPi improves UPDRS motor success also to non-human primate models of PD [122]. Striatal scores by about 33% [113, 114] and reduces the time spent in ”off” AADC gene transfer using adeno-associated viral vectors has been by 30% to 60%, without any substantial reduction in L-DOPA proposed as a method to locally increase the capacity for DA equivalent doses [115]. GPi-DBS exerts a potent effect on production, with the aim of reducing the dose requirement for dyskinesias that is unrelated to reductions in L-DOPA dosage and peripheral L-DOPA. The method has been well characterized in stable over at least 3-4 years [116, 117]. The surgical risks are non-human primate models of PD [123]. This particular approach comparable to those of STN-DBS, but the stimulation-related side might be useful for reducing non-motor side effects of L-DOPA effects seem to be less common [117]. Stimulation of the GPi is pharmacotherapy, in particular, the psychiatric complications mainly chosen when dyskinesias are the major problem and/or to related to high DA levels in mesolimbic regions. A phase I safety minimize the risk of cognitive side effects in older patients who trial has shown that rAAV-AADC treatment is well tolerated and need functional neurosurgery. results in sustained putaminal transgene expression [124]. Analysis of the clinical data from this study pointed to a modest Thalamotomy and thalamic stimulation are very effective improvement, although the nonblinded assessments and the absence against parkinsonian tremor, but have little efficacy on other motor of a control group preclude a definite interpretation of these results symptoms and are therefore seldom used in advanced PD patients. [124].

FUTURE TREATMENT OPTIONS A third option for viral vector mediated in vivo gene delivery is by triple enzyme replacement (TH, GHC1, AADC) to completely Gene Therapy to Provide Continuous Dopaminergic Stimulation restore DA production in targeted cells. Encouraging results have Before discussing non-dopaminergic drug targets, we first come from preclinical studies using a type of lentiviral vector briefly review the most recent strategy for CDS, which consists in (equine infectious anemia virus, EIAV) with triple enzyme restoring the enzymatic machinery to produce DOPA and DA in the delivery, both in rats [125, 126] and in non-human primates [127]. striatum either by implanting genetically modified cells (ex vivo These successful experimental results have prompted a phase I/II gene transfer) or by viral vector-mediated gene delivery to resident clinical trial in PD [128]. Bilateral injections of the EIAV virus cells (in vivo gene transfer). carrying the three genes required for DA synthesis are made in the putamen of PD patients, and preliminary reports have presented The precursor of DA synthesis in the brain is L-tyrosine, an encouraging results [129]. In summary, viral vector-mediated gene essential amino acid supplied by a normal diet. L-tyrosine is transfer of enzymes required for DA synthesis appears to be a very converted to DA by two enzymatic steps. It is first converted to promising avenue to a CDS therapy in PD. This approach will DOPA by the enzyme tyrosine hydroxylase (TH), which requires however entail all the risks and potential problems associated with a the co-factor tetrahydrobiopterin (BH4) in its reduced form. The neurosurgical intervention. reduced form of BH4 is synthetized from guanosine triphosphate (GTP) in a three step enzymatic reaction catalyzed by GTP Treatments Targeting Non-Dopaminergic Systems cyclohydrolase 1 (GCH1), which is rate-limiting, and other enzymes that are ubiquitously expressed in all cell types (reviewed One proposed approach to prevent or treat motor complications in [118]). The TH enzyme is exclusively expressed by consists in adding non-dopaminergic drugs to the standard L-DOPA dopaminergic cells, and GCH1 is mainly located in dopaminergic pharmacotherapy (Table 3). This approach appears particularly and terminals of the striatum. The second step of DA promising to reduce the severity of peak-dose dyskinesia and/or to synthesis is catalyzed by aromatic amino-acid decarboxylase prolong the time spent in a good “on” condition upon L-DOPA (AADC). The majority of AADC is found in dopaminergic and dosing. In addition, some non-dopaminergic treatments may serotonergic fibers, but the enzyme is expressed also in other cell ameliorate psychiatric or cognitive symptoms that are L-DOPA- types, such as glial cells, endothelial cells and striatal neurons resistant [58, 130]. To this day, the clinical evaluation of non- (reviewed in [22]). This extranigral AADC activity explains why dopaminergic drugs has not yet delivered any concrete, new the capacity for decarboxylation of exogenous L-DOPA is therapeutic options for PD. However, several new compounds are maintained even after a severe nigrostriatal lesion (reviewed in now being evaluated for their antidyskinetic efficacy in phase I/II to [118]). phase III clinical trials with some promising results. Here we review the most important categories of non-dopaminergic targets, The in vivo gene transfer approach has yielded very which are attracting great interest on the part of both basic scientists encouraging results in preclinical animal models of PD, and is now and pharmaceutical companies.

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Table 3. Non-Dopaminergic Compounds Reducing L-DOPA-Induced Dyskinesia in Animal Models of PD (Partial Listing)

Target System Compound Name Proposed Target and Mechanism Species Seminal References

Amantadine NMDA-R antagonism Mouse, rat, macaque [168, 181, 252, 253] CP-101,606 NR2B-specific NMDA-R antagonism Macaque [145] MPEP mGluR5 antagonism Rat, macaque [151, 153, 155]

GLUTAMATE MTEP mGluR5 antagonism Rat, macaque [151, 152, 155] Fenobam mGluR5 antagonism Rat, macaque [156] Topiramate AMPA/Kainate-R antagonism Rat, macaque [134]

Calcium-permeable AMPA-R IEM 1460 Rat, marmoset [133] antagonism

Clozapine 5-HT2/6-R (and D4R) antagonism Rat, macaque [168, 181, 182]

Buspirone 5-HT1A-R partial agonism Mouse, rat [168, 169, 252] SEROTONIN 5-HT1A-R partial agonism Macaque [254] 8-OH-DPAT and CP- 5-HT - and 5-HT -R agonism Rat, macaque [163, 173, 175, 255] 94253 1A 1B

Idazoxan  Adrenoceptor antagonism Rat, macaque [168, 191, 193] NORADRENALINE Fipamezole 2C Adrenoceptor antagonism Marmoset [192]

ADENOSINE Istradefylline (KW-6002) Adenosine A2A-R antagonism Macaque [217] HISTAMINE Immepip, Imetit Histamine H3-R agonism Marmoset [256] Mouse, rat, squirrel ACETYLCHOLINE Nicotine Nicotinic-R desensitization [246, 247, 250, 257] monkey

Glutamate Receptors receptor type 5 (mGluR5), which is abundantly expressed in striatal Glutamate neurotransmission is involved in L-DOPA-induced neurons and becomes upregulated following chronic dyskinesia at multiple pathophysiological levels (reviewed in [22, dyskinesiogenic treatment with L-DOPA [150, 151]. The first 23, 131]). In particular, glutamate receptors are critically involved reports of antidyskinetic efficacy came from the rat model of L- in the synaptic and molecular alterations of striatal neurons that DOPA-induced dyskinesia, in which mGluR5 antagonists were have been found to occur in dyskinetic animals (reviewed in [21]). shown to both prevent the development of abnormal involuntary The possibility to treat L-DOPA-induced dyskinesia by inhibiting movements and acutely reduce their severity [148, 152-154]. These ionotropic glutamate receptors was proposed by Thomas Chase and effects were accompanied by a normalization of molecular and collaborators more than 10 years ago [60, 132]. Indeed, compounds neurochemical changes that are closely associated with the with antagonistic properties at N-methyl-D-aspartate (NMDA) or movement disorder [148, 152-154]. Antidyskinetic effects of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) different mGluR5 antagonists were then reported also in receptors have shown antidyskinetic efficacy in animal experiments parkinsonian monkeys [155, 156]. Interestingly, two phase-II [133-135] and in small clinical trials in PD patients [136-138]. As clinical trials of a Novartis mGluR5 antagonist in patients with PD previously mentioned, amantadine, an anti-infectious agent that have reported a significant improvement of L-DOPA-induced exerts weak non-competitive antagonism at the NMDA receptor dyskinesia [157]. Although modulation of other types of mGluR [139], is the only non-dopaminergic drug currently used for the (group II and III in particular) has been suggested to be beneficial, clinical management of L-DOPA-induced dyskinesia [140-143]. this pharmacological approach has not yet delivered any promising The NR2B subunit of the NMDA receptor is abundantly expressed antidyskinetic effect in animal studies [148, 158]. in striatal neurons, and shows an altered subcellular distribution in the rat model of L-DOPA-induced dyskinesia [144]. NMDA Serotonin Receptors receptor antagonists that selectively interact with the NR2B subunit Growing experimental evidence implicates the brain serotonin have been shown to prevent the development of dyskinesia in a (5-HT) system in the pathophysiology of L-DOPA-induced non-human primate model of PD [145] and to alleviate dyskinesia dyskinesia. Serotonin receptors are expressed both postsynaptically in a small clinical trial in PD patients [146]. However, widely and presynaptically in striatal neurons, where they modulate discrepant results have been produced by this category of signaling pathways downstream of DA receptors [159, 160]. compounds in the preclinical literature, ranging between Moreover, serotonin neurons provide the main route of L-DOPA improvement [147], to no effect [148], to aggravation [149] of L- uptake and conversion in the brain when the nigrostriatal DA DOPA-induced abnormal involuntary movements. These data projection is severely compromised [161, 162]. These neurons lack would suggest that the clinical outcome of NR2B antagonist high-affinity DA reuptake mechanisms and DA autoreceptors in treatment is heavily influenced by the structure/activity profiles of their axon terminals, thus turning into a source of unregulated DA the specific compounds used and by the particular types of release after the administration of L-DOPA (reviewed in [22]). The dyskinesias that need to be treated. causal implication of serotonin neurons in LID is proven by the A growing number of studies in both rodent and non-human dramatic reduction in dyskinesia severity engendered by 5-HT- primates models of L-DOPA-induced dyskinesia have reported specific lesions either in the forebrain [163] or in the midbrain promising results using antagonists of metabotropic glutamate raphe nuclei [164]. 676 CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 Cenci et al.

Agonists of 5-HT1A autoreceptors blunt the increase in striatal following L-DOPA administration, giving presynaptic 2A- extracellular DA levels induced by L-DOPA [165, 166] and adrenoceptors a false signal [188]. Furthermore, a recent study has attenuate the severity of dyskinesia [167-169]. Substances with shown that local infusion of NA in the 6-OHDA-lesioned rat agonistic activity at the 5-HT1A receptor have shown antidyskinetic striatum can by itself induce dyskinesia [189]. Several studies in rat efficacy also in small clinical trials in PD patients [170, 171]. and primate models of PD have shown that antagonists of 2B/C- However, these promising results were not replicated in a large adrenoceptors are effective in reducing dyskinesia and can prolong double-blind, placebo-controlled trial of the 5-HT1A agonist, the antiakinetic effect of single L-DOPA doses [168, 181, 190-192]. sarizotan [172]. Negative results in the latter trial may have One potential underlying mechanism may involve a reduction of depended on insufficient drug dosage, which in turn may have been extracellular levels of DOPA and DA, which the 2C adrenoceptor dictated by the need to avoid adverse events. Indeed, all the antagonist idazoxan has been shown to achieve at a dose that currently available 5-HT1A agonists can potentially interfere with significantly reduced the severity of dyskinesia in rats [193]. the antiparkinsonian action of L-DOPA if given at sufficiently high Antagonists of 1-adrenoceptors have been recently evaluated doses [166, 173]. To circumvent this problem, Carta and Björklund in animal models of L-DOPA-induced dyskinesia, and found to be have proposed to treat dyskinesia using a combination of 5-HT1A effective in rats [194], whereas they seem to merely attenuate L- and 5-HT1B receptor agonists [174]. Because of their synergistic DOPA-induced hyperactivity but not dyskinesia in MPTP-lesioned antidyskinetic effect, the two classes of compounds can be given at macaques [195]. The main limitation to the clinical use of - relatively low doses, thus minimizing the risk of adverse effects that adrenoceptor antagonists is given by potential adverse effects on the are due to a stimulation of post-synaptic 5-HT1A and 5-HT1B autonomic nervous system. Clinical trials with idazoxan in receptors (described in e.g. [166]). Combined antidyskinetic dyskinetic PD patients have indeed reported cardiovascular side treatment with 5-HT1A and 5-HT1B agonists was first tested in 6- effects, such as flushing, headache, tachychardia, and hypertension OHDA-lesioned rats [163] and then in MPTP-lesioned macaques [196]. [175], achieving an antidyskinetic effect similar in magnitude to that of a lesion of forebrain serotonin projections [163]. Another Adenosine Receptors possible option would consist in finding compounds that combine a 5-HT1A agonistic profile with stimulatory properties on DA Several neuromodulators within the basal ganglia are likely to receptors. One compound fulfilling this profile seems to be be implicated in L-DOPA-induced motor complications. Among piclozotan [176]. A phase II clinical trial of piclozotan in PD these, adenosine, opioids, and endocannabinoids are reviewed here patients with motor complications (defining “on” time without because they are currently the focus of therapeutic development dyskinesia as the primary outcome measure) has just been programs. completed (http://clinicaltrials.gov/ct2/show/NCT00623363), and Adenosine receptors represent attractive targets for non- results should be made publicly available soon. dopaminergic antiparkinsonian therapies (recently reviewed by Among older drugs targeting 5-HT receptors, a particular [197, 198]). Adenosine A1 and A2A receptors are widely expressed mention should be given to the drug, throughout the brain. The expression of A2A is particularly , which has shown antidyskinetic efficacy first in small abundant in the striatum, where this receptor shows both open-labeled trials [177, 178] and then in a larger double-blind presynaptic and postsynaptic localizations. In the striatum, post- placebo-controlled clinical trial in PD [179]. Reductions in synaptic A2A receptors are expressed in GABAergic medium spiny dyskinesia severity and duration were achieved by clozapine at projection neurons of the indirect pathway [199, 200]. This gives doses that did not interfere with the therapeutic benefit provided by adenosine A2A receptors an important regulatory influence on L-DOPA. This effect was thus attributed to the antagonistic striatopallidal GABAergic transmission, which is mediated through properties of clozapine at 5-HT rather than DA receptors [177, multiple cellular mechanisms [201]. Functionally, the adenosine 179]. Indeed, clozapine has low nanomolar affinity for serotonin 5- A2A receptor is linked to both D2 and mGluR5 receptors [202], with HT1A, 5-HT2 and 5-HT6 receptors [180]. From a translational which it can heterodimerize [203, 204]. Indeed, high-resolution viewpoint, it is worth noting that treatment with clozapine has been immunoelectron microscopy has revealed that the three receptors shown to reduce L-DOPA-induced abnormal involuntary co-distribute within the extrasynaptic plasma membrane of the movements in both rat [168, 181] and non-human primate models same dendritic spines of asymmetrical (putative glutamatergic) of PD [182]. A wider clinical application of clozapine may be striatal synapses [205]. Adenosine A2A receptor stimulation limited by the risk of severe haematologic side effects, decreases the binding affinity of D2 receptors for DA [206, 207]. At agranulocytosis in particular (https://www.clozapineregistry.com/ the downstream signalling levels, A2A stimulation counters D2 insert.pdf.ashx). receptor-mediated inhibition of cAMP formation, activating nuclear signaling pathways and the expression of immediate early genes in Adrenergic Receptors striatopallidal neurons [159, 208, 209]. Noradrenaline (NA) is an important neuromodulator in all brain Preclinical studies have demonstrated that adenosine A2A regions, including the basal ganglia. It exerts its effects by antagonists have anti-akinetic properties in both rodent [210, 211] interacting with adrenergic receptors (also called adrenoceptors), and non-human primate models of PD [212, 213]. This anti-akinetic which are G-protein-coupled receptors belonging to two main effect has been attributed to an inhibitory action on the groups,  and , each including several subtypes. The 2C- striatopallidal pathway [214]. Great interest has been raised by the adrenoceptor subtype is abundantly expressed in the basal ganglia, potential use of A2A antagonists as an antiparkinsonian treatment. and particularly in the striatum, globus pallidus and substantia nigra Moreover, antagonism of A2A receptors has been proposed as a pars reticulata (SNr) [183, 184]. In the striatum, alpha2c- treatment for L-DOPA-induced dyskinesia by several authors adrenoceptors are localized on GABAergic medium-sized spiny (reviewed in [215]). Supporting such a proposal, a human post projection neurons (but not on interneurons) and they may modulate mortem study showed increased putaminal expression of the A2A both the direct and indirect striatofugal pathways [185]. The receptor mRNA in dyskinetic PD patients compared to non- important role played by alpha2c- and 1 adrenoceptors in the dyskinetic cases [216]. Moreover, coadministration of an A2A modulation of GABA release and neuronal excitability in the basal receptor antagonist (KW-6002) with apomorphine was shown to ganglia [186, 187] warrants focus on these receptors as targets for prevent the development of dyskinesias in MPTP-treated primates antidyskinetic and antiparkinsonian therapies. Another reason to be [217]. More recently, conditional ablation of forebrain A2A interested in this system is that L-DOPA is a precursor of both DA receptors was found to attenuate L-DOPA-induced dyskinesia in 6- and NA. Hence brain levels of NA are expected to increase OHDA lesioned mice [218]. However, studies in 6-OHDA-lesioned Treatment of Dyskinesia and Motor Fluctuations in Parkinson’s Disease CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 677 rats indicated that A2A receptor antagonists do not have any (reviewed in [242]). Recent studies in rodent models have provided intrinsic antidyskinetic activity and prevent dyskinesia only to the novel mechanistic insights into the role of endocannabinoids in L- extent that they allow for a reduction in L-DOPA dosage [219]. DOPA-induced dyskinesia [243, 244]. In rats with 6-OHDA This prediction is consistent with the overall results of clinical lesions, a pharmacologically induced elevation of endocannabinoid studies performed thus far. levels was found to attenuate L-DOPA-induced abnormal involuntary movements only when the transient receptor-potential Several compounds with antagonistic activity at the A2A receptor have been evaluated clinically. The frontrunner among vanilloid subtype (TRPV1) was blocked. These and other data these is KW-6002 (istradefylline), which demonstrated promising indicated that the stimulation of CB-R and TRPV1 by anti-parkinsonian efficacy in phase II trials [212, 220-223]. In these endocannabinoids has opposite effects on dyskinetic behaviours trials, istradefylline increased “on” time and reduced “off” time in [244]. patients with motor fluctuations on L-DOPA medication [221, 224]. Some additional neuromodulators have been recently raising However, further phase III trials showed mixed results, and a attention as potential targets for antidyskinetic treatments (partially worsening of dyskinesia occurred in advanced PD patients, reviewed in [245]). The recent report that nicotine administration although dyskinesias were reported as being “non-troublesome”. improves L-DOPA-induced dyskinesia in both rats and monkeys Other publicly announced A2A antagonists in the pipeline are, [246, 247] has stimulated novel lines of investigation on the role of Preladenant (SCH420814), BIIB014 (V2006) and ST-1535 [225]. acetylcholine nicotinic receptors in PD. This class of receptors represents an attractive target for drug development because of the In summary, adenosine A2A receptor antagonists remain a major candidate for antiparkinsonian drug development. Although these potential neuroprotective and cognitive-enhancing properties of compounds do not by themselves reduce the severity of already nicotinic receptor modulators (reviewed in [248]). Current research established dyskinesias, they have a “DOPA-sparing” effect in efforts in this area are focused on dissecting the role of specific experimental models of PD and therefore may prevent the receptor subtypes [249], and recent results show that the development of dyskinesia and motor fluctuations when given as an antidyskinetic effect of nicotine is mediated by 2 nicotinic early adjunct treatment to L-DOPA. This early combined treatment receptors [250]. may indeed prevent the maladaptive neuroplasticity induced by standard dosing regimens with L-DOPA [198], a suggestion that CONCLUDING REMARKS needs to be specifically addressed in future experimental studies. During the past few years, significant advances have been made in defining and optimizing strategies for continuous dopaminergic Other Neuromodulatory Systems stimulation in PD. Subcutaneous apomorphine infusion or enteric Opioid peptides, such as enkephalins and dynorphins, modulate L-DOPA delivery are already available to PD patients in several GABAergic and glutamatergic neurotransmission at several sites European countries and represent a valid alternative to DBS when within the basal ganglia-thalamo-cortical networks. Changes in functional neurosurgery is either contraindicated or poorly opioid receptor binding indicative of enhanced opioid transmission accessible. Moreover, CDS may offer some distinctive advantages, have shown a strong association with dyskinesia in both animal as it does not worsen the patients’ cognitive status and may even models of PD [226, 227] and dyskinetic PD patients [228, 229]. improve some non-motor features of PD (in particular, non-motor Although the latter association was discovered several years ago, “off” periods and sleep problems). Novel approaches to CDS based the precise mechanisms through which endogenous opioids on gene therapy are being explored in animal models of PD with contribute to dyskinesia remain to be studied. Opioid receptors are successful results. CDS by infusion therapy or gene therapy is, abundantly expressed in the basal ganglia, particularly the delta and however, relatively invasive and expensive, and does not represent the mu subtypes [226], and antagonists of these receptor classes the only avenue to the treatment of motor fluctuations and have been shown to alleviate L-DOPA-induced dyskinesia in dyskinesia. Adjunct pharmacological treatments to prevent or treat MPTP-lesioned primates [230, 231]. However, agonists of opioid L-DOPA-induced motor complications will thus have a useful role receptors also can reduce dyskinesia in both monkey and rat models in the management of PD. Even on this front, research has made of PD [232, 233]. These apparently contradictory results are not great progress during the past few years thanks to the availability of surprising given the intricate neurobiology of opioid novel and predictive animal models of L-DOPA-induced neurotransmission. Opioid peptides can produce opposite dyskinesia, which have fostered mechanistic investigations and behavioural and cellular effects depending on their concentration, therapeutic discoveries. site of action, and interactions with non-opioid receptor systems Multiple interesting targets and compounds with antidyskinetic [234, 235]. The poor mechanistic understanding of opioid receptor efficacy have been recently identified in animal studies. In our modulators in L-DOPA-induced dyskinesia limits the scientific view, approaches suitable for clinical development should fulfill the interest in this class of compound as an approach to treatment. following criteria, (i) high-quality preclinical assessment using The endocannabinoid system consists of signalling lipids multiple behavioural tests that can rule out false positive effects (endocannabinoids) and their allied cannabinoid receptors (CB-R), (due, in particular, to a possible motor depressant action of the which are particularly abundant in the basal ganglia. The drug/dose tested), (ii) reproducibility of the antidyskinetic effect endocannabinoid anandamide is released by striatal neurons across laboratories and animal models, and (iii) sufficient following dopamine D2 receptor stimulation, and this response was pharmacodynamic-pharmacokinetic information to establish a link proposed to act as an inhibitory feed-back mechanism countering between the observed antidyskinetic effect and the level of target DA-induced facilitation of motor activity [236]. The widespread occupancy by the drug of interest. The latter assessment would rule distribution of CB-Rs at both pre- and post-synaptic sites within the out false negative effects due to insufficient dosage or poor brain basal ganglia suggests, however, that the endocannabinoid system exposure. There is still debate on the assessment methods that has additional and more complex roles. Cannabinoid receptor should be used to test antidyskinetic treatments in human studies. agonists can indeed activate movement when locally administered Importantly, the M. J. Fox Foundation for Parkinson’s research in the striatum and SNr [237, 238], and inhibit movement when (www.michaeljfox. org/research) is supporting an ongoing clinical administered in the subthalamic nucleus or the globus pallidus trial that will compare different dyskinesia rating methods against [239-241]. It is therefore not surprising that both agonists and the reference compound, amantadine. The results of this study will antagonists of CB-R have been found to alleviate L-DOPA-induced provide very useful guidelines for designing clinical trials of dyskinesia in PD patients and non-human primate models of PD antidyskinetic treatments in the future.

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ABBREVIATIONS [11] Manson, A.; Schrag, A. In Recent Breakthroughs in Basal Ganglia Research. Bezard, E., Ed.; Nova Science Publishers Inc.: New York, AADC = Amino-acid decarboxylase NY, 2006, pp. 369-380. AAV = Adeno-associated viral vectors [12] Mazzella, L.; Yahr, M.D.; Marinelli, L.; Huang, N.; Moshier, E.; Di Rocco A. Dyskinesias predict the onset of motor response fluctuations AMPA = 3-hydroxy-5-methyl-4-isoxazole proprionic acid in patients with Parkinson's disease on L-dopa monotherapy. BH4 = Co-factor tetrahydrobiopetrin Parkinsonism Relat. Disord., 2005, 11, 151-155. CDS = Continuous dopaminergic stimulation [13] Nutt, J.G. In Drug-induced Movement Disorders. Lang, A.E.; Weiner, W.J., Eds.; Futura Publishing Co., Inc.: Mount Kisko, 1992, pp. 281- DA = Dopamine 314. EIAV = Equine infectious anemia virus [14] Luquin, M.R.; Scipioni, O.; Vaamonde, J.; Gershanik, O.; Obeso, J.A. Levodopa-induced dyskinesias in Parkinson's disease: clinical and GCH1 = GTP cyclohydrolase 1 pharmacological classification. Mov. Disord., 1992, 7, 117-124. GPi = Globus pallidus [15] Marsden, C.D.; Parkes, J.D.; Quinn, N. In Movement Disorders. Marsden, C.D.; Fahn, S., Eds.; Butterworths: London, 1981, pp. 96- GTP = Guanosine triphosphate 122. 5-HT = 5-hydroxy-; serotonin [16] Quinn, N.P. Classification of fluctuations in patients with Parkinson's KW-6002 = Istradefylline disease. Neurology, 1998, 51, S25-S29. [17] Nyholm, D.; Lennernas, H.; Gomes-Trolin, C.; Aquilonius, S.M. LID = L-DOPA-induced dyskinesias Levodopa pharmacokinetics and motor performance during activities of LCIG = L-DOPA-carbidopa intestinal gel daily living in patients with Parkinson's disease on individual drug combinations. Clin. Neuropharmacol., 2002, 25, 89-96. L-DOPA = Levodopa; L-3,4-dihydroxyphenylalanine [18] Calabresi, P.; Giacomini, P.; Centonze, D.; Bernardi, G. Levodopa- mGluR5 = Metabotropic glutamate receptor type 5 induced dyskinesia: a pathological form of striatal synaptic plasticity? Ann. Neurol., 2000, 47, S60-S68; discussion S68-S69. MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [19] Linazasoro, G. New ideas on the origin of L-dopa-induced dyskinesias: NMDA = N-methyl-D-aspartate age, genes and neural plasticity. Trends Pharmacol. Sci., 2005, 26, 391- 397. NA = Noradrenaline; norepinephrine [20] Prescott, I.A.; Dostrovsky, J.O.; Moro, E.; Hodaie, M.; Lozano, A.M.; 6-OHDA = 6-hydroxy-dopamine Hutchison, W.D. Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients. Brain, PD = Parkinson’s disease 2009, 132, 309-318. PEG = Percutaneous endoscopic gastrostomy [21] Cenci, M.A.; Konradi, C. Maladaptive striatal plasticity in L-DOPA- rAAV = Recombinant adeno-associated virus induced dyskinesia. Prog. Brain Res., 2010, 183, 209-233. [22] Cenci, M.A.; Lundblad, M. Post- versus presynaptic plasticity in L- R = Receptor (in Table 3) DOPA-induced dyskinesia. J. Neurochem., 2006, 99, 381-392. SCH420814 = Preladenant [23] Cenci, M.A.; Lindgren, H.S. Advances in understanding L-DOPA- induced dyskinesia. Curr. Opin. Neurobiol., 2007, 17, 665-671. STN = Subthalamic nucleus [24] Rascol, O.; Payoux, P.; Ory, F.; Ferreira, J.J.; Brefel-Courbon, C.; TH = Tyrosine hydroxylase Montastruc, J.L. Limitations of current Parkinson's disease therapy. Ann. Neurol., 2003, 53(Suppl. 3), S3-S12. TRPV1 = Transient receptor-potential vanilloid subtype [25] Giovannoni, G.; O'Sullivan, J.D.; Turner, K.; Manson, A.J.; Lees, A.J. Hedonistic homeostatic dysregulation in patients with Parkinson's REFERENCES disease on dopamine replacement therapies. J. Neurol. Neurosurg. [1] Mercuri, N.B.; Bernardi, G. The 'magic' of L-dopa: why is it the gold Psychiatry, 2000, 68, 423-428. standard Parkinson's disease therapy? Trends Pharmacol. Sci., 2005, [26] Schrag, A. Psychiatric aspects of Parkinson's disease--an update. J. 26, 341-344. Neurol., 2004, 251, 795-804. [2] Cenci, M.A.; Odin, P. In Cortico-subcortical dynamics in Parkinson´s [27] Chaudhuri, K.R.; Schapira, A.H. Non-motor symptoms of Parkinson's disease. Tseng, K.-Y., Ed.; Humana Press and Springer Editorials, disease: dopaminergic pathophysiology and treatment. Lancet Neurol., 2009, 309-334. 2009, 8, 464-474. [3] Hoehn, M.M. Parkinson's disease: progression and mortality. Adv. [28] Schapira, A.H.; Olanow, C.W. Neuroprotection in Parkinson disease: Neurol., 1987, 45, 457-461. mysteries, myths, and misconceptions. JAMA, 2004, 291, 358-364. [4] Hoehn, M.M. Result of chronic levodopa therapy and its modification [29] Pahwa, R.; Lyons, K.E. Levodopa-related wearing-off in Parkinson's by bromocriptine in Parkinson's disease. Acta Neurol. Scand., 1985, 71, disease: identification and management. Curr. Med. Res. Opin., 2009, 97-106. 25, 841-849. [5] Rivera-Calimlim, L.; Dujovne, C.A.; Morgan, J.P.; Lasagna, L.; [30] Obeso, J.A.; Grandas, F.; Vaamonde, J.; Luquin, M.R.; Artieda, J.; Bianchine, J.R. Absorption and metabolism of L-dopa by the human Lera, G.; Rodriguez, M.E.; Martinez-Lage, J.M. Motor complications stomach. Eur. J. Clin. Invest., 1971, 1, 313-320. associated with chronic levodopa therapy in Parkinson's disease. [6] Bianchine, J.R.; Calimlim, L.R.; Morgan, J.P.; Dujuvne, C.A.; Lasagna, Neurology, 1989, 39, 11-19. L. Metabolism and absorption of L-3,4 dihydroxyphenylalanine in [31] Dupont, E.; Andersen, A.; Boas, J.; Boisen, E.; Borgmann, R.; patients with Parkinson's disease. Ann. NY Acad. Sci., 1971, 179, 126- Helgetveit, A.C.; Kjaer, M.O.; Kristensen, T.N.; Mikkelsen, B.; 140. Pakkenberg, H.; Presthus, J.; Stien, R.; Worm-Petersen, J.; Buch, D. [7] Cedarbaum, J.M. Clinical pharmacokinetics of anti-parkinsonian drugs. Sustained-release Madopar HBS compared with standard Madopar in Clin. Pharmacokinet., 1987, 13, 141-178. the long-term treatment of de novo parkinsonian patients. Acta Neurol. [8] Calne, D.B.; Reid, J.L.; Vakil, S.D.; Rao, S.; Petrie, A.; Pallis, C.A.; Scand., 1996, 93, 14-20. Gawler, J.; Thomas, P.K.; Hilson, A. Idiopathic Parkinsonism treated [32] Stowe, R.; Ives, N.; Clarke, C.; van Hilten, J.; Ferreira, J.; Hawker, R.J.; with an extracerebral decarboxylase inhibitor in combination with Shah, L.; Wheatley, K.; Gray, R. Dopamine agonist therapy in early levodopa. Br. Med. J., 1971, 3, 729-732. Parkinson's disease. Cochrane Database Syst. Rev., 2008, CD006564. [9] Nutt, J.G.; Holford, N.H. The response to levodopa in Parkinson's [33] Antonini, A.; Tolosa, E.; Mizuno, Y.; Yamamoto, M.; Poewe, W.H. A disease: imposing pharmacological law and order. Ann. Neurol., 1996, reassessment of risks and benefits of dopamine agonists in Parkinson's 39, 561-573. disease. Lancet Neurol., 2009, 8, 929-937. [10] Ahlskog, J.E.; Muenter, M.D. Frequency of levodopa-related [34] Guttman, M. Double-blind comparison of pramipexole and dyskinesias and motor fluctuations as estimated from the cumulative bromocriptine treatment with placebo in advanced Parkinson's disease. literature. Mov. Disord., 2001, 16, 448-458. International Pramipexole-Bromocriptine Study Group. Neurology, 1997, 49, 1060-1065. Treatment of Dyskinesia and Motor Fluctuations in Parkinson’s Disease CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 679

[35] Lieberman, A.; Olanow, C.W.; Sethi, K.; Swanson, P.; Waters, C.H.; and restoration of nigrostriatal dopamine neurons in post-MPTP- Fahn, S.; Hurtig, H.; Yahr, M. A multicenter trial of ropinirole as induced parkinsonism. Neurobiol. Dis., 2007, 25, 35-44. adjunct treatment for Parkinson's disease. Ropinirole Study Group. [53] Youdim, M.B.; Bakhle, Y.S. Monoamine oxidase: isoforms and Neurology, 1998, 51, 1057-1062. inhibitors in Parkinson's disease and depressive illness. Br. J. [36] Potenza, M.N.; Voon, V.; Weintraub, D. Drug Insight: impulse control Pharmacol., 2006, 147(Suppl. 1), S287-S296. disorders and dopamine therapies in Parkinson's disease. Nat. Clin. [54] Olanow, C.W.; Rascol, O.; Hauser, R.; Feigin, P.D.; Jankovic, J.; Lang, Pract. Neurol., 2007, 3, 664-672. A.; Langston, W.; Melamed, E.; Poewe, W.; Stocchi, F.; Tolosa, E.; [37] Shill, H.; Stacy, M. Respiratory function in Parkinson's disease. Clin. ADAGIO Study Investigators. A double-blind, delayed-start trial of Neurosci., 1998, 5, 131-135. rasagiline in Parkinson's disease. N. Engl. J. Med., 2009, 361, 1268- [38] Schade, R.; Andersohn, F.; Suissa, S.; Haverkamp, W.; Garbe, E. 1278. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl. [55] Palhagen, S.; Heinonen, E.; Hagglund, J.; Kaugesaar, T.; Maki-Ikola, J. Med., 2007, 356, 29-38. O.; Palm, R.; Swedish Parkinson Study Group. Selegiline slows the [39] Zanettini, R.; Antonini, A.; Gatto, G.; Gentile, R.; Tesei, S.; Pezzoli G. progression of the symptoms of Parkinson disease. Neurology, 2006, Valvular heart disease and the use of dopamine agonists for Parkinson's 66, 1200-1206. disease. N Engl. J. Med., 2007, 356, 39-46. [56] Zesiewicz, T.A.; Sullivan, K.L.; Hauser, R.A. Levodopa-induced [40] Steiger, M.; Jost, W.; Grandas, F.; Van Camp, G. Risk of valvular heart dyskinesia in Parkinson's disease: epidemiology, etiology, and disease associated with the use of dopamine agonists in Parkinson's treatment. Curr. Neurol. Neurosci. Rep., 2007, 7, 302-310. disease: a systematic review. J. Neural Transm., 2009, 116, 179-191. [57] Danysz, W.; Parsons, C.G.; Kornhuber, J.; Schmidt, W.J.; Quack, G. [41] Fitzgerald, L.W.; Burn, T.C.; Brown, B.S.; Patterson, J.P.; Corjay, Aminoadamantanes as NMDA receptor antagonists and M.H.; Valentine, P.A.; Sun, J.H.; Link, J.R.; Abbaszade, I.; Hollis, J.M.; antiparkinsonian agents--preclinical studies. Neurosci. Biobehav. Rev., Largent, B.L.; Hartig, P.R.; Hollis, G.F.; Meunier, P.C.; Robichaud, 1997, 21, 455-468. A.J.; Robertson, D.W. Possible role of valvular serotonin 5-HT(2B) [58] Aarsland, D.; Ballard, C.; Walker, Z.; Bostrom, F.; Alves, G.; receptors in the cardiopathy associated with . Mol. Kossakowski, K.; Leroi, I.; Pozo-Rodriguez, F.; Minthon, L.; Londos, Pharmacol., 2000, 57, 75-81. E. Memantine in patients with Parkinson's disease dementia or [42] Rothman, R.B.; Baumann, M.H.; Savage, J.E.; Rauser, L.; McBride, dementia with Lewy bodies: a double-blind, placebo-controlled, A.; Hufeisen, S.J.; Roth, B.L. Evidence for possible involvement of 5- multicentre trial. Lancet Neurol., 2009, 8, 613-618. HT(2B) receptors in the cardiac valvulopathy associated with [59] Lokk, J. Memantine can relieve certain symptoms in Parkinson disease. fenfluramine and other serotonergic medications. Circulation, 2000, Improvement achieved in two out of three described cases with 102, 2836-2841. dyskinesia and cognitive failure. Lakartidningen, 2004, 101, 2003- [43] Antonini, A.; Poewe, W. Fibrotic heart-valve reactions to dopamine- 2006. agonist treatment in Parkinson's disease. Lancet Neurol., 2007, 6, 826- [60] Chase, T.N. Levodopa therapy: consequences of the nonphysiologic 829. replacement of dopamine. Neurology, 1998, 50, S17-S25. [44] Rakshi, J.S.; Pavese, N.; Uema, T.; Ito, K.; Morrish, P.K.; Bailey, D.L.; [61] Nyholm, D. The rationale for continuous dopaminergic stimulation in Brooks, D.J. A comparison of the progression of early Parkinson's advanced Parkinson's disease. Parkinsonism Relat. Disord., 2007, disease in patients started on ropinirole or L-dopa: an 18F-dopa PET 13(Suppl.), S13-S17. study. J. Neural Transm., 2002, 109, 1433-1443. [62] Olanow, C.W.; Agid, Y.; Mizuno, Y.; Albanese, A.; Bonuccelli, U.; [45] Holloway, R.G.; Shoulson, I.; Fahn, S.; Kieburtz, K.; Lang, A.; Marek, Damier, P.; De Yebenes, J.; Gershanik, O.; Guttman, M.; Grandas, F.; K.; McDermott, M.; Seibyl, J.; Weiner, W.; Musch, B.; Kamp, C.; Hallett, M.; Hornykiewicz, O.; Jenner, P.; Katzenschlager, R.; Welsh, M.; Shinaman, A.; Pahwa, R.; Barclay, L.; Hubble, J.; LeWitt, Langston, W.J.; LeWitt, P.; Melamed, E.; Mena, M.A.; Michel, P.P.; P.; Miyasaki, J.; Suchowersky, O.; Stacy, M.; Russell, D.S.; Ford, B.; Mytilineou, C.; Obeso, J.A.; Poewe, W.; Quinn, N.; Raisman-Vozari, Hammerstad, J.; Riley, D.; Standaert, D.; Wooten, F.; Factor, S.; R.; Rajput, A.H.; Rascol, O.; Sampaio, C.; Stocchi, F. Levodopa in the Jankovic, J.; Atassi, F.; Kurlan, R.; Panisset, M.; Rajput, A.; Rodnitzky, treatment of Parkinson's disease: current controversies. Mov. Disord., R.; Shults, C.; Petsinger, G.; Waters, C.; Pfeiffer, R.; Biglan, K.; 2004, 19, 997-1005. Borchert, L.; Montgomery, A.; Sutherland, L.; Weeks, C.; DeAngelis, [63] de la Fuente-Fernandez, R.; Sossi, V.; Huang, Z.; Furtado, S.; Lu, J.Q.; M.; Sime, E.; Wood, S.; Pantella, C.; Harrigan, M.; Fussell, B.; Dillon, Calne, D.B.; Ruth, T.J.; Stoessl, A.J. Levodopa-induced changes in S.; Alexander-Brown, B.; Rainey, P.; Tennis, M.; Rost-Ruffner, E.; synaptic dopamine levels increase with progression of Parkinson's Brown, D.; Evans, S.; Berry, D.; Hall, J.; Shirley, T.; Dobson, J.; disease: implications for dyskinesias. Brain, 2004, 127, 2747-2754. Fontaine, D.; Pfeiffer, B.; Brocht, A.; Bennett, S.; Daigneault, S.; [64] Pavese, N.; Evans, A.H.; Tai, Y.F.; Hotton, G.; Brooks, D.J.; Lees, A.J.; Hodgeman, K.; O'Connell, C.; Ross, T.; Richard, K.; Watts, A.; Piccini, P. Clinical correlates of levodopa-induced dopamine release in Parkinson Study Group. Pramipexole vs levodopa as initial treatment Parkinson disease: a PET study. Neurology, 2006, 67, 1612-1617. for Parkinson disease: a 4-year randomized controlled trial. Arch. [65] Blanchet, P.J.; Calon, F.; Martel, J.C.; Bedard, P.J.; Di Paolo, T.; Neurol., 2004, 61, 1044-1053. Walters, R.R.; Piercey, M.F. Continuous administration decreases and [46] Schapira, A.H. Molecular and clinical pathways to neuroprotection of pulsatile administration increases behavioral sensitivity to a novel dopaminergic drugs in Parkinson disease. Neurology, 2009, 72, S44- dopamine D2 agonist (U-91356A) in MPTP-exposed monkeys. J. S50. Pharmacol. Exp. Ther., 1995, 272, 854-859. [47] Fernandez, H.H.; Chen, J.J. Monoamine oxidase-B inhibition in the [66] Shoulson, I.; Glaubiger, G.A.; Chase, T.N. On-off response. Clinical treatment of Parkinson's disease. Pharmacotherapy, 2007, 27, 174S- and biochemical correlations during oral and intravenous levodopa 185S. administration in parkinsonian patients. Neurology, 1975, 25, 1144- [48] Bonifacio, M.J.; Palma, P.N.; Almeida, L.; Soares-da-Silva, P. 1148. Catechol-O-methyltransferase and its inhibitors in Parkinson's disease. [67] Quinn, N.; Marsden, C.D.; Parkes, J.D. Complicated response CNS Drug Rev., 2007, 13, 352-379. fluctuations in Parkinson's disease: response to intravenous infusion of [49] Hauser, R.A.; Panisset, M.; Abbruzzese, G.; Mancione, L.; Dronamraju, levodopa. Lancet, 1982, 2, 412-415. N.; Kakarieka, A.; FIRST-STEP Study Group. Double-blind trial of [68] Kurlan, R.; Rubin, A.J.; Miller, C.; Rivera-Calimlim, L.; Clarke, A.; levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Shoulson, I. Duodenal delivery of levodopa for on-off fluctuations in Parkinson's disease. Mov. Disord., 2009, 24, 541-550. parkinsonism: preliminary observations. Ann. Neurol., 1986, 20, 262- [50] Seeberger, L.C.; Hauser, R.A. Levodopa/carbidopa/entacapone in 265. Parkinson's disease. Expert Rev. Neurother., 2009, 9, 929-940. [69] Nyholm, D.; Aquilonius, S.M. Levodopa infusion therapy in Parkinson [51] Rascol, O.; Brooks, D.J.; Melamed, E.; Oertel, W.; Poewe, W.; Stocchi, disease: state of the art in 2004. Clin. Neuropharmacol., 2004, 27, 245- F.; Tolosa, E.; LARGO study group. Rasagiline as an adjunct to 256. levodopa in patients with Parkinson's disease and motor fluctuations [70] Nyholm, D. Enteral levodopa/carbidopa gel infusion for the treatment (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given of motor fluctuations and dyskinesias in advanced Parkinson's disease. Once daily, study): a randomised, double-blind, parallel-group trial. Expert Rev. Neurother., 2006, 6 , 1403-1411. Lancet, 2005, 365, 947-954. [71] Nyholm, D. Pharmacokinetic optimisation in the treatment of [52] Sagi, Y.; Mandel, S.; Amit, T.; Youdim, M.B. Activation of tyrosine Parkinson's disease: an update. Clin. Pharmacokinet., 2006, 45, 109- kinase receptor signaling pathway by rasagiline facilitates neurorescue 136. 680 CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 Cenci et al.

[72] Nyholm, D.; Nilsson Remahl, A.I.; Dizdar, N.; Constantinescu, R.; [94] Stocchi, F.; Bramante, L.; Monge, A.; Viselli, F.; Baronti, F.; Stefano, Holmberg, B.; Jansson, R.; Aquilonius, S.M.; Askmark, H. Duodenal E.; Ruggieri, S. Apomorphine and lisuride infusion. A comparative levodopa infusion monotherapy vs oral polypharmacy in advanced chronic study. Adv. Neurol., 1993, 60, 653-655. Parkinson disease. Neurology, 2005, 64, 216-223. [95] Katzenschlager, R.; Hughes, A.; Evans, A.; Manson, A.J.; Hoffman, [73] Eggert, K.; Schrader, C.; Hahn, M.; Stamelou, M.; Rüssmann, A.; M.; Swinn, L.; Watt, H.; Bhatia, K.; Quinn, N.; Lees, A.J. Continuous Dengler, R.; Oertel, W.; Odin, P. Continuous jejunal levodopa infusion subcutaneous apomorphine therapy improves dyskinesias in Parkinson's in patients with advanced Parkinson´s disease: Practical aspects and disease: a prospective study using single-dose challenges. Mov. Disord., outcome of motor and non-motor complications. Clin. 2005, 20, 151-157. Neuropharmacol., 2008, 31(3), 151-166. [96] Manson, A.J.; Turner, K.; Lees, A.J. Apomorphine monotherapy in the [74] Antonini, A.; Isaias, I.U.; Canesi, M.; Zibetti, M.; Mancini, F.; treatment of refractory motor complications of Parkinson's disease: Manfredi, L.; Dal Fante, M.; Lopiano, L.; Pezzoli, G. Duodenal long-term follow-up study of 64 patients. Mov. Disord., 2002, 17, 1235- levodopa infusion for advanced Parkinson's disease: 12-month 1241. treatment outcome. Mov. Disord., 2007, 22, 1145-1149. [97] Kolls, B.J.; Stacy, M. Apomorphine: a rapid rescue agent for the [75] Antonini, A.; Mancini, F.; Canesi, M.; Zangaglia, R.; Isaias, I.U.; management of motor fluctuations in advanced Parkinson disease. Clin. Manfredi, L.; Pacchetti, C.; Zibetti, M.; Natuzzi, F.; Lopiano, L.; Nappi, Neuropharmacol., 2006, 29, 292-301. G.; Pezzoli, G. Duodenal levodopa infusion improves quality of life in [98] Stacy, M.; Silver, D. Apomorphine for the acute treatment of "off" advanced Parkinson's disease. Neurodegener. Dis., 2008, 5, 244-246. episodes in Parkinson's disease. Parkinsonism Relat. Disord., 2008, 14, [76] Devos, D. Patient profile, indications, efficacy and safety of duodenal 85-92. levodopa infusion in advanced Parkinson's disease. Mov. Disord., 2009, [99] Baldwin, C.M.; Keating, G.M. Rotigotine transdermal patch: a review 24, 993-1000. of its use in the management of Parkinson's disease. CNS Drugs, 2007, [77] Honig, H.; Antonini, A.; Martinez-Martin, P.; Forgacs, I.; Faye, G.C.; 21, 1039-1055. Fox, T.; Fox, K.; Mancini, F.; Canesi, M.; Odin, P.; Chaudhuri, K.R. [100] Rascol, O.; Perez-Lloret, S. Rotigotine transdermal delivery for the Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter treatment of Parkinson's disease. Expert Opin. Pharmacother., 2009, study of effects on nonmotor symptoms and quality of life. Mov. 10, 677-691. Disord., 2009, 24, 1468-1474. [101] Steiger, M. Constant dopaminergic stimulation by transdermal delivery [78] Raudino, F.; Garavaglia, P.; Pianezzola, C.; Riboldazzi, G.; Leva, S.; of dopaminergic drugs: a new treatment paradigm in Parkinson's Guidotti, M.; Bono, G. Long-term experience with continuous duodenal disease. Eur. J. Neurol., 2008, 15, 6-15. levodopa-carbidopa infusion (Duodopa): report of six patients. Neurol. [102] Priano, L.; Albani, G.; Calderoni, S.; Baudo, S.; Lopiano, L.; Rizzone, Sci., 2009, 30, 85-86. M.; Astolfi, V.; Cavalli, R.; Gasco, M.R.; Fraschini, F.; Bergamasco, [79] Nyholm, D.; Jansson, R.; Willows, T.; Remahl, I.N. Long-term 24-hour B.; Mauro, A. Controlled-release transdermal apomorphine treatment duodenal infusion of levodopa: outcome and dose requirements. for motor fluctuations in Parkinson's disease. Neurol. Sci., 2002, Neurology, 2005, 65, 1506-1507. 23(Suppl. 2), S99-S100. [80] Schwab, R.S.; Amador, L.V.; Lettvin, J.Y. Apomorphine in Parkinson's [103] Woitalla, D.; Muller, T.; Benz, S.; Horowski, R.; Przuntek, H. disease. Trans. Am. Neurol. Assoc., 1951, 56, 251-253. Transdermal lisuride delivery in the treatment of Parkinson's disease. J. [81] Corsini, G.U.; Del Zompo, M.; Gessa, G.L.; Mangoni, A. Therapeutic Neural Transm. Suppl., 2004, 89-95. efficacy of apomorphine combined with an extracerebral inhibitor of [104] Deuschl, G.; Schade-Brittinger, C.; Krack, P.; Volkmann, J.; Schafer, dopamine receptors in Parkinson's disease. Lancet, 1979, 1, 954-956. H.; Bötzel, K.; Daniels, C.; Deutschländer, A.; Dillmann, U.; Eisner, [82] Frankel, J.P.; Lees, A.J.; Kempster, P.A.; Stern, G.M. Subcutaneous W.; Gruber, D.; Hamel, W.; Herzog, J.; Hilker, R.; Klebe, S.; Kloss, M.; apomorphine in the treatment of Parkinson's disease. J. Neurol. Koy, J.; Krause, M.; Kupsch, A.; Lorenz, D.; Lorenzl, S.; Mehdorn, Neurosurg. Psychiatry, 1990, 53, 96-101. H.M.; Moringlane, J.R.; Oertel, W.; Pinsker, M.O.; Reichmann, H.; [83] Stibe, C.; Lees, A.; Stern, G. Subcutaneous infusion of apomorphine Reuss, A.; Schneider, G.H.; Schnitzler, A.; Steude, U.; Sturm, V.; and lisuride in the treatment of parkinsonian on-off fluctuations. Lancet, Timmermann, L.; Tronnier, V.; Trottenberg, T.; Wojtecki, L.; Wolf, E.; 1987, 1, 871. Poewe, W.; Voges, J.; German Parkinson Study Group; [84] Gancher, S. Pharmacokinetics of apomorphine in Parkinson's disease. J. Neurostimulation Section. A randomized trial of deep-brain stimulation Neural Transm. Suppl., 1995, 45, 137-141. for Parkinson's disease. N. Engl. J. Med., 2006, 355, 896-908. [85] Hagell, P.; Odin, P. Apomorphine in the treatment of Parkinson's [105] Weaver, F.M.; Follett, K.; Stern, M.; Hur, K.; Harris, C.; Marks, W.J., disease. J. Neurosci. Nurs., 2001, 33, 21-34, 37-38. Jr.; Rothlind, J.; Sagher, O.; Reda, D.; Moy, C.S.; Pahwa, R.; Burchiel, [86] O'Sullivan, J.D.; Lees, A.J. Use of apomorphine in Parkinson's disease. K.; Hogarth, P.; Lai, E.C.; Duda, J.E.; Holloway, K.; Samii, A.; Horn, Hosp. Med., 1999, 60, 816-820. S.; Bronstein, J.; Stoner, G.; Heemskerk, J.; Huang, G.D.; CSP 468 [87] Pollak, P.; Champay, A.S.; Gaio, J.M.; Hommel, M.; Benabid, A.L.; Study Group. Bilateral deep brain stimulation vs best medical therapy Perret, J. Subcutaneous administration of apomorphine in motor for patients with advanced Parkinson disease: a randomized controlled fluctuations in Parkinson's disease. Rev. Neurol. (Paris), 1990, 146, trial. JAMA, 2009, 301, 63-73. 116-122. [106] Krack, P.; Batir, A.; Van Blercom, N.; Chabardes, S.; Fraix, V.; [88] Hagell, P.; Odin, P.; Shing, M. In Apomorphine in Parkinson´s Disease. Ardouin, C.; Koudsie, A.; Limousin, P.D.; Benazzouz, A.; LeBas, J.F.; Hagell, P.; Odin, P.; Shing, M., Eds.; Uni-Med Verlag AG: Bremen, Benabid, A.L.; Pollak, P. Five-year follow-up of bilateral stimulation of Germany, 2005, pp. 369-380. the subthalamic nucleus in advanced Parkinson's disease. N. Engl. J. [89] Chaudhuri, K.R.; Critchley, P.; Abbott, R.J.; Pye, I.F.; Millac, P.A. Med., 2003, 349, 1925-1934. Subcutaneous apomorphine for on-off oscillations in Parkinson's [107] Kleiner-Fisman, G.; Herzog, J.; Fisman, D. N.; Tamma, F.; Lyons, disease. Lancet, 1988, 2, 1260. K. E.; Pahwa, R.; Lang, A. E.; Deuschl, G. Subthalamic nucleus [90] Hughes, A.J.; Bishop, S.; Kleedorfer, B.; Turjanski, N.; Fernandez, W.; deep brain stimulation: summary and meta-analysis of outcomes. Lees, A.J.; Stern, G.M. Subcutaneous apomorphine in Parkinson's Mov. Disord., 2006, 21 (Suppl 14), S290-304. disease: response to chronic administration for up to five years. Mov. [108] Follett, K.A. Comparison of pallidal and subthalamic deep brain Disord., 1993, 8, 165-170. stimulation for the treatment of levodopa-induced dyskinesias. [91] Kanovsky, P.; Kubova, D.; Bares, M.; Hortova, H.; Streitova, H.; Neurosurg. Focus, 2004, 17, E3. Rektor, I.; Znojil, V. Levodopa-induced dyskinesias and continuous [109] Voges, J.; Hilker, R.; Botzel, K.; Kiening, K.L.; Kloss, M.; Kupsch, A.; subcutaneous infusions of apomorphine: results of a two-year, Schnitzler, A.; Schneider, G.H.; Steude, U.; Deuschl, G.; Pinsker, M.O. prospective follow-up. Mov. Disord., 2002, 17, 188-191. Thirty days complication rate following surgery performed for deep- [92] Morgante, L.; Basile, G.; Epifanio, A.; Spina, E.; Antonini, A.; Stocchi, brain-stimulation. Mov. Disord., 2007, 22, 1486-1489. F.; Di Rosa, E.; Martino, G.; Marconi, R.; La Spina, P.; Nicita-Mauro, [110] Witt, K.; Daniels, C.; Reiff, J.; Krack, P.; Volkmann, J.; Pinsker, M.O.; V.; Di Rosa, A.E. Continuous apomorphine infusion (CAI) and Krause, M.; Tronnier, V.; Kloss, M.; Schnitzler, A.; Wojtecki, L.; neuropsychiatric disorders in patients with advanced Parkinson's Bötzel, K.; Danek, A.; Hilker, R.; Sturm, V.; Kupsch, A.; Karner, E.; disease: a follow-up of two years. Arch. Gerontol. Geriatr. Suppl., Deuschl, G. Neuropsychological and psychiatric changes after deep 2004, 291-296. brain stimulation for Parkinson's disease: a randomised, multicentre [93] Pietz, K.; Hagell, P.; Odin, P. Subcutaneous apomorphine in late stage study. Lancet Neurol., 2008, 7, 605-614. Parkinson's disease: a long term follow up. J. Neurol. Neurosurg. [111] Heo, J.H.; Lee, K.M.; Paek, S.H.; Kim, M.J.; Lee, J.Y.; Kim, J.Y.; Cho, Psychiatry, 1998, 65, 709-716. S.Y.; Lim, Y.H.; Kim, M.R.; Jeong, S.Y.; Jeon, B.S. The effects of Treatment of Dyskinesia and Motor Fluctuations in Parkinson’s Disease CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 681

bilateral subthalamic nucleus deep brain stimulation (STN DBS) on production, and functional improvement in a rat model of Parkinson's cognition in Parkinson disease. J. Neurol. Sci., 2008, 273, 19-24. disease. J. Neurosci., 2002, 22, 10302-10312. [112] Voon, V.; Krack, P.; Lang, A.E.; Lozano, A.M.; Dujardin, K.; [127] Jarraya, B.; Boulet, S.; Ralph, G.S.; Jan, C.; Bonvento, G.; Azzouz, M.; Schüpbach, M.; D'Ambrosia, J.; Thobois, S.; Tamma, F.; Herzog, J.; Miskin, J.E.; Shin, M.; Delzescaux, T.; Drouot, X.; Hérard, A.S.; Day, Speelman, J.D.; Samanta, J.; Kubu, C.; Rossignol, H.; Poon, Y.Y.; D.M.; Brouillet, E.; Kingsman, S.M.; Hantraye, P.; Mitrophanous, Saint-Cyr, J.A.; Ardouin, C.; Moro, E. A multicentre study on suicide K.A.; Mazarakis, N.D.; Palfi, S. Dopamine gene therapy for Parkinson's outcomes following subthalamic stimulation for Parkinson's disease. disease in a nonhuman primate without associated dyskinesia. Sci. Brain, 2008, 131, 2720-2728. Transl. Med., 2009, 1, 2ra4. [113] Stefani, A.; Lozano, A.M.; Pepp.e, A.; Stanzione, P.; Galati, S.; [128] Oxford Biomedica. Oxford Biomedica initiates phase I/II trial of Tropepi, D.; Pierantozzi, M.; Brusa, L.; Scarnati, E.; Mazzone, P. ProSavin® gene-based treatment for Parkinson's Disease, 2007. Bilateral deep brain stimulation of the pedunculopontine and [129] Oxford Biomedica. Oxford Biomedica announces update On Pase I/II subthalamic nuclei in severe Parkinson's disease. Brain, 2007, 130, study Of ProSavin® In Parkinson's Disease. 2009. 1596-1607. [130] Schapira, A.H.; Bezard, E.; Brotchie, J.; Calon, F.; Collingridge, G.L.; [114] Volkmann, J.; Allert, N.; Voges, J.; Sturm, V.; Schnitzler, A.; Freund, Ferger, B.; Hengerer, B.; Hirsch, E.; Jenner, P.; Le Novère, N.; Obeso, H.J. Long-term results of bilateral pallidal stimulation in Parkinson's J.A.; Schwarzschild, M.A.; Spampinato, U.; Davidai, G. Novel disease. Ann. Neurol., 2004, 55, 871-875. pharmacological targets for the treatment of Parkinson's disease. Nat. [115] Anderson, V.C.; Burchiel, K.J.; Hogarth, P.; Favre, J.; Hammerstad, Rev. Drug Discov., 2006, 5, 845-854. J.P. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson [131] Cenci, M.A. Dopamine dysregulation of movement control in L- disease. Arch. Neurol., 2005, 62, 554-560. DOPA-induced dyskinesia. Trends Neurosci., 2007, 30, 236-243. [116] Moro, E.; Lozano, A.M.; Pollak, P.; Agid, Y.; Rehncrona, S.; [132] Chase, T.N.; Oh, J.D.; Blanchet, P.J. Neostriatal mechanisms in Volkmann, J.; Kulisevsky, J.; Obeso, J.A.; Albanese, A.; Hariz, M.I.; Parkinson's disease. Neurology, 1998, 51, S30-S35. Quinn, N.P.; Speelman, J.D.; Benabid, A.L.; Fraix, V.; Mendes, A.; [133] Kobylecki, C.; Cenci, M.A.; Crossman, A.R.; Ravenscroft, P. Calcium- Welter, M.L.; Houeto, J.L.; Cornu, P.; Dormont, D.; Tornqvist, A.L.; permeable AMPA receptors are involved in the induction and Ekberg, R.; Schnitzler, A.; Timmermann, L.; Wojtecki, L.; Gironell, A.; expression of L-DOPA-induced dyskinesia in Parkinson's disease. J. Rodriguez-Oroz, M.C.; Guridi, J.; Bentivoglio, A.R.; Contarino, M.F.; Neurochem., 2010, 114(2), 499-511. Romito, L.; Scerrati, M.; Janssens, M.; Lang, A.E. Long-term results of [134] Konitsiotis, S.; Blanchet, P.J.; Verhagen Metman, L.; Lamers, E.; a multicenter study on subthalamic and pallidal stimulation in Chase, T.N. AMPA receptor blockade improves levodopa-induced Parkinson's disease. Mov. Disord., 25(5), 578-586. dyskinesia in MPTP monkeys. Neurology, 2000, 54, 1589-1595. [117] Rodriguez-Oroz, M.C.; Obeso, J.A.; Lang, A.E.; Houeto, J.L.; Pollak, [135] Papa, S.M.; Chase, T.N. Levodopa-induced dyskinesias improved by a P.; Rehncrona, S.; Kulisevsky, J.; Albanese, A.; Volkmann, J.; Hariz, glutamate antagonist in Parkinsonian monkeys. Ann. Neurol., 1996, 39, M.I.; Quinn, N.P.; Speelman, J.D.; Guridi, J.; Zamarbide, I.; Gironell, 574-578. A.; Molet, J.; Pascual-Sedano, B.; Pidoux, B.; Bonnet, A.M.; Agid, Y.; [136] Chase, T.N.; Oh, J.D.; Konitsiotis, S. Antiparkinsonian and Xie, J.; Benabid, A.L.; Lozano, A.M.; Saint-Cyr, J.; Romito, L.; antidyskinetic activity of drugs targeting central glutamatergic Contarino, M.F.; Scerrati, M.; Fraix, V.; Van Blercom, N. Bilateral mechanisms. J. Neurol., 2000, 247(Suppl. 2), 1136-1142. deep brain stimulation in Parkinson's disease: a multicentre study with 4 [137] Verhagen Metman, L.; Blanchet, P.J.; van den Munckhof, P.; Del years follow-up. Brain, 2005, 128, 2240-2249. Dotto, P.; Natte, R.; Chase, T.N. A trial of dextromethorphan in [118] Carlsson, T.; Bjorklund, T.; Kirik, D. Restoration of the striatal parkinsonian patients with motor response complications. Mov. Disord., dopamine synthesis for Parkinson's disease: viral vector-mediated 1998, 13, 414-417. enzyme replacement strategy. Curr. Gene Ther., 2007, 7, 109-120. [138] Verhagen Metman, L.; Del Dotto, P.; Natte, R.; van den Munckhof, P.; [119] Kirik, D.; Georgievska, B.; Burger, C.; Winkler, C.; Muzyczka, N.; Chase, T.N. Dextromethorphan improves levodopa-induced Mandel, R.J.; Bjorklund, A. Reversal of motor impairments in dyskinesias in Parkinson's disease. Neurology, 1998, 51, 203-206. parkinsonian rats by continuous intrastriatal delivery of L-dopa using [139] Kornhuber, J.; Weller, M.; Schopp.meyer, K.; Riederer, P. Amantadine rAAV-mediated gene transfer. Proc. Natl. Acad. Sci. USA, 2002, 99, and memantine are NMDA receptor antagonists with neuroprotective 4708-4713. properties. J. Neural Transm. Suppl., 1994, 43, 91-104. [120] Carlsson, T.; Winkler, C.; Burger, C.; Muzyczka, N.; Mandel, R.J.; [140] Metman, L.V.; Del Dotto, P.; LePoole, K.; Konitsiotis, S.; Fang, J.; Cenci, A.; Björklund, A.; Kirik, D. Reversal of dyskinesias in an animal Chase, T.N. Amantadine for levodopa-induced dyskinesias: a 1-year model of Parkinson's disease by continuous L-DOPA delivery using follow-up study. Arch. Neurol., 1999, 56, 1383-1386. rAAV vectors. Brain, 2005, 128, 559-569. [141] Luginger, E.; Wenning, G.K.; Bosch, S.; Poewe, W. Beneficial effects [121] Bjorklund, T.; Carlsson, T.; Cederfjall, E.A.; Carta, M.; Kirik, D. of amantadine on L-dopa-induced dyskinesias in Parkinson's disease. Optimized adeno-associated viral vector-mediated striatal DOPA Mov. Disord., 2000, 15, 873-878. delivery restores sensorimotor function and prevents dyskinesias in a [142] Del Dotto, P.; Pavese, N.; Gambaccini, G.; Bernardini, S.; Metman, model of advanced Parkinson's disease. Brain, 133, 496-511. L.V.; Chase, T.N.; Bonuccelli, U. Intravenous amantadine improves [122] Palfi, S. Towards gene therapy for Parkinson's disease. Lancet Neurol., levadopa-induced dyskinesias: an acute double-blind placebo-controlled 2008, 7, 375-376. study. Mov. Disord., 2001, 16, 515-520. [123] Bankiewicz, K.S.; Eberling, J.L.; Kohutnicka, M.; Jagust, W.; Pivirotto, [143] Blanchet, P.J.; Metman, L.V.; Chase, T.N. Renaissance of amantadine P.; Bringas, J.; Cunningham, J.; Budinger, T.F.; Harvey-White, J. in the treatment of Parkinson's disease. Adv. Neurol., 2003, 91, 251-257. Convection-enhanced delivery of AAV vector in parkinsonian [144] Gardoni, F.; Picconi, B.; Ghiglieri, V.; Polli, F.; Bagetta, V.; Bernardi, monkeys; in vivo detection of gene expression and restoration of G.; Cattabeni, F.; Di Luca, M.; Calabresi, P. A critical interaction dopaminergic function using pro-drug approach. Exp. Neurol., 2000, between NR2B and MAGUK in L-DOPA induced dyskinesia. J. 164, 2-14. Neurosci., 2006, 26, 2914-2922. [124] Eberling, J.L.; Jagust, W.J.; Christine, C.W.; Starr, P.; Larson, P.; [145] Hadj Tahar, A.; Gregoire, L.; Darre, A.; Belanger, N.; Meltzer, L.; Bankiewicz, K.S.; Aminoff, M.J. Results from a phase I safety trial of Bédard, P.J. Effect of a selective glutamate antagonist on L-dopa- hAADC gene therapy for Parkinson disease. Neurology, 2008, 70(21), induced dyskinesias in drug-naive parkinsonian monkeys. Neurobiol. 1980-1983. Dis., 2004, 15, 171-176. [125] Shen, Y.; Muramatsu, S.I.; Ikeguchi, K.; Fujimoto, K.I.; Fan, D.S.; [146] Nutt, J.G.; Gunzler, S.A.; Kirchhoff, T.; Hogarth, P.; Weaver, J.L.; Ogawa, M.; Mizukami, H.; Urabe, M.; Kume, A.; Nagatsu, I.; Urano, Krams, M.; Jamerson, B.; Menniti, F.S.; Landen, J.W. Effects of a F.; Suzuki, T.; Ichinose, H.; Nagatsu, T.; Monahan, J.; Nakano, I.; NR2B selective NMDA glutamate antagonist, CP-101,606, on Ozawa, K. Triple transduction with adeno-associated virus vectors dyskinesia and Parkinsonism. Mov. Disord., 2008, 23, 1860-1866. expressing tyrosine hydroxylase, aromatic-L-amino-acid decarboxylase, [147] Blanchet, P.J.; Konitsiotis, S.; Whittemore, E.R.; Zhou, Z.L.; and GTP cyclohydrolase I for gene therapy of Parkinson's disease. Woodward, R.M.; Chase, T.N. Differing effects of N-methyl-D- Hum. Gene Ther., 2000, 11, 1509-1519. aspartate receptor subtype selective antagonists on dyskinesias in [126] Azzouz, M.; Martin-Rendon, E.; Barber, R.D.; Mitrophanous, K.A.; levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys. J. Carter, E.E.; Rohll, J.B.; Kingsman, S.M.; Kingsman, A.J.; Mazarakis, Pharmacol. Exp. Ther., 1999, 290, 1034-1040. N.D. Multicistronic lentiviral vector-mediated striatal gene transfer of [148] Rylander, D.; Recchia, A.; Mela, F.; Dekundy, A.; Danysz, W.; Cenci, aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP M.A. Pharmacological modulation of glutamate transmission in a rat cyclohydrolase I induces sustained transgene expression, dopamine 682 CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 Cenci et al.

model of L-DOPA-induced dyskinesia: effects on motor behavior and exogenously administered L-DOPA in the striatum with nigrostriatal striatal nuclear signaling. J. Pharmacol. Exp. Ther., 2009, 330, 227-235. denervation. J. Neurochem., 2001, 76, 1346-1353. [149] Nash, J.E.; Ravenscroft, P.; McGuire, S.; Crossman, A.R.; Menniti, [166] Lindgren, H.S.; Andersson, D.R.; Lagerkvist, S.; Nissbrandt, H.; Cenci, F.S.; Brotchie, J.M. The NR2B-selective NMDA receptor antagonist M.A. L-DOPA-induced dopamine efflux in the striatum and the CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides substantia nigra in a rat model of Parkinson's disease: temporal and mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP- quantitative relationship to the expression of dyskinesia. J. Neurochem., lesioned marmoset model of Parkinson's disease. Exp. Neurol., 2004, 2010, 112, 1465-1476. 188, 471-479. [167] Bishop, C.; Taylor, J.L.; Kuhn, D.M.; Eskow, K.L.; Park, J.Y.; Walker, [150] Konradi, C.; Westin, J.E.; Carta, M.; Eaton, M.E.; Kuter, K.; Dekundy, P.D. MDMA and fenfluramine reduce L-DOPA-induced dyskinesia via A.; Lundblad, M.; Cenci, M.A. Transcriptome analysis in a rat model of indirect 5-HT1A receptor stimulation. Eur. J. Neurosci., 2006, 23, L-DOPA-induced dyskinesia. Neurobiol. Dis., 2004, 17, 219-236. 2669-2676. [151] Samadi, P.; Gregoire, L.; Morissette, M.; Calon, F.; Hadj Tahar, A.; [168] Dekundy, A.; Lundblad, M.; Danysz, W.; Cenci, M.A. Modulation of Dridi, M.; Belanger, N.; Meltzer, L.T.; Bédard, P.J.; Di Paolo, T. L-DOPA-induced abnormal involuntary movements by clinically tested mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP compounds: further validation of the rat dyskinesia model. Behav. monkeys. Neurobiol. Aging, 2008, 29(7), 1040-1051. Brain Res., 2007, 179, 76-89. [152] Mela, F.; Marti, M.; Dekundy, A.; Danysz, W.; Morari, M.; Cenci, [169] Eskow, K.L.; Gupta, V.; Alam, S.; Park, J.Y.; Bishop, C. The partial 5- M.A. Antagonism of metabotropic glutamate receptor type 5 attenuates HT(1A) agonist reduces the expression and development of l-DOPA-induced dyskinesia and its molecular and neurochemical l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy. correlates in a rat model of Parkinson's disease. J. Neurochem., 2007, Pharmacol. Biochem. Behav., 2007, 87, 306-314. 101, 483-497. [170] Bonifati, V.; Fabrizio, E.; Cipriani, R.; Vanacore, N.; Meco, G. [153] Levandis, G.; Bazzini, E.; Armentero, M.T.; Napp.i, G.; Blandini, F. Buspirone in levodopa-induced dyskinesias. Clin. Neuropharmacol., Systemic administration of an mGluR5 antagonist, but not unilateral 1994, 17, 73-82. subthalamic lesion, counteracts l-DOPA-induced dyskinesias in a [171] Olanow, C.W.; Damier, P.; Goetz, C.G.; Mueller, T.; Nutt, J.; Rascol, rodent model of Parkinson's disease. Neurobiol. Dis., 2008, 29(1), 161- O.; Serbanescu, A.; Deckers, F.; Russ, H. Multicenter, open-label, trial 168. of sarizotan in Parkinson disease patients with levodopa-induced [154] Yamamoto, N.; Soghomonian, J.J. Metabotropic glutamate mGluR5 dyskinesias (the SPLENDID Study). Clin. Neuropharmacol., 2004, 27, receptor blockade opp.oses abnormal involuntary movements and the 58-62. increases in glutamic acid decarboxylase mRNA levels induced by l- [172] Goetz, C.G.; Damier, P.; Hicking, C.; Laska, E.; Muller, T.; Olanow, DOPA in striatal neurons of 6-hydroxydopamine-lesioned rats. C.W.; Rascol, O.; Russ, H. Sarizotan as a treatment for dyskinesias in Neuroscience, 2009, 163, 1171-1180. Parkinson's disease: a double-blind placebo-controlled trial. Mov. [155] Morin, N.; Gregoire, L.; Gomez-Mancilla, B.; Gasparini, F.; Di Paolo, Disord., 2007, 22, 179-186. T. Effect of the metabotropic glutamate receptor type 5 antagonists [173] Iravani, M.M.; Tayarani-Binazir, K.; Chu, W.B.; Jackson, M.J.; Jenner, MPEP and MTEP in parkinsonian monkeys. Neuropharmacology, P. In 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-treated primates, 2010, 58(7), 981-986. the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT [156] Rylander, D.; Iderberg, H.; Li, Q.; Dekundy, A.; Zhang, J.; Li, H.; inhibits levodopa-induced dyskinesia but only with increased motor Baishen, R.; Danysz, W.; Bezard, E.; Cenci, M.A. A mGluR5 disability. J. Pharmacol. Exp. Ther., 2006, 319, 1225-1234. antagonist under clinical development improves L-DOPA-induced [174] Carta, M.; Carlsson, T.; Munoz, A.; Kirik, D.; Bjorklund, A. Serotonin- dyskinesia in parkinsonian rats and monkeys. Neurobiol. Dis., 2010, dopamine interaction in the induction and maintenance of L-DOPA- 39(3), 352-361. induced dyskinesias. Prog. Brain Res., 2008, 172, 465-478. [157] Berg, D.; Godau, J.; Trenkwalder, C.; Eggert, K.; Csoti, I.; Storch, A.; [175] Munoz, A.; Li, Q.; Gardoni, F.; Marcello, E.; Qin, C.; Carlsson, T.; Huber, H.; Morelli-Canelo, M.; Stamelou, M.; Ries, V.; Wolz, M.; Kirik, D.; Di Luca, M.; Björklund, A.; Bezard, E.; Carta, M. Combined Schneider, C.; Di Paolo, T.; Gasparini, F.; Hariry, S.; 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA- Vandemeulebroecke, M.; Abi-Saab, W.; Cooke, K.; Johns, D.; Gomez- induced dyskinesia. Brain, 2008, 131, 3380-3394. Mancilla, B. AFQ056 treatment of levodopa-induced dyskinesias: [176] Kamei, K.; Maeda, N.; Nomura, K.; Shibata, M.; Katsuragi-Ogino, R.; Results of 2 randomized controlled trials. Mov. Disord., 26, 1243-1250. Koyama, M.; Nakajima, M.; Inoue, T.; Ohno, T.; Tatsuoka, T. [158] Bonsi, P.; Cuomo, D.; Picconi, B.; Sciamanna, G.; Tscherter, A.; Tolu, Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine M.; Bernardi, G.; Calabresi, P.; Pisani, A. Striatal metabotropic derivatives as selective 5-HT1A receptor agonists with neuroprotective glutamate receptors as a target for pharmacotherapy in Parkinson's effect: Discovery of Piclozotan. Bioorg. Med. Chem., 2006, 14, 1978- disease. Amino Acids, 2007, 32, 189-195. 1992. [159] Svenningsson, P.; Tzavara, E.T.; Liu, F.; Fienberg, A.A.; Nomikos, [177] Bennett, J.P., Jr.; Landow, E.R.; Schuh, L.A. Suppression of G.G.; Greengard, P. DARPP.-32 mediates serotonergic dyskinesias in advanced Parkinson's disease. II. Increasing daily neurotransmission in the forebrain. Proc. Natl. Acad. Sci. USA, 2002, clozapine doses suppress dyskinesias and improve parkinsonism 99, 3188-3193. symptoms. Neurology, 1993, 43, 1551-1555. [160] Zhang, X.; Andren, P.E.; Greengard, P.; Svenningsson, P. Evidence for [178] Pierelli, F.; Adipietro, A.; Soldati, G.; Fattapposta, F.; Pozzessere, G.; a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA Scoppetta, C. Low dosage clozapine effects on L-dopa induced treatment of an animal model of Parkinsonism. Proc. Natl. Acad. Sci. dyskinesias in parkinsonian patients. Acta Neurol. Scand., 1998, 97, USA, 2008, 105, 2163-2168. 295-299. [161] Tanaka, H.; Kannari, K.; Maeda, T.; Tomiyama, M.; Suda, T.; [179] Durif, F.; Debilly, B.; Galitzky, M.; Morand, D.; Viallet, F.; Borg, M.; Matsunaga, M. Role of serotonergic neurons in L-DOPA-derived Thobois, S.; Broussolle, E.; Rascol, O. Clozapine improves dyskinesias extracellular dopamine in the striatum of 6-OHDA-lesioned rats. in Parkinson disease: a double-blind, placebo-controlled study. Neuroreport, 1999, 10, 631-634. Neurology, 2004, 62, 381-388. [162] Maeda, T.; Nagata, K.; Yoshida, Y.; Kannari, K. Serotonergic [180] Meltzer, H.Y. An overview of the mechanism of action of clozapine. J. hyperinnervation into the dopaminergic denervated striatum Clin. Psychiatry, 1994, 55(Suppl. B), 47-52. compensates for dopamine conversion from exogenously administered [181] Lundblad, M.; Andersson, M.; Winkler, C.; Kirik, D.; Wierup, N.; l-DOPA. Brain Res., 2005, 1046, 230-233. Cenci, M.A. Pharmacological validation of behavioural measures of [163] Carta, M., Carlsson, T., Kirik, D., Bjorklund, A. Dopamine released akinesia and dyskinesia in a rat model of Parkinson's disease. Eur. J. from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in Neurosci., 2002, 15, 120-132. Parkinsonian rats. Brain, 2007, 130, 1819-1833. [182] Grondin, R.; Doan, V.D.; Gregoire, L.; Bedard, P.J. D1 receptor [164] Eskow, K.L.; Dupre, K.B.; Barnum, C.J.; Dickinson, S.O.; Park, J.Y.; blockade improves L-dopa-induced dyskinesia but worsens Bishop, C. The role of the dorsal raphe nucleus in the development, parkinsonism in MPTP monkeys. Neurology, 1999, 52, 771-776. expression, and treatment of L-dopa-induced dyskinesia in [183] Scheinin, M.; Lomasney, J.W.; Hayden-Hixson, D.M.; Schambra, hemiparkinsonian rats. Synapse, 2009, 63, 610-620. U.B.; Caron, M.G.; Lefkowitz, R.J.; Fremeau, R.T., Jr. Distribution of [165] Kannari, K.; Yamato, H.; Shen, H.; Tomiyama, M.; Suda, T.; alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Matsunaga, M. Activation of 5-HT(1A) but not 5-HT(1B) receptors Res. Mol. Brain Res., 1994, 21, 133-149. attenuates an increase in extracellular dopamine derived from Treatment of Dyskinesia and Motor Fluctuations in Parkinson’s Disease CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 683

[184] Nicholas, A.P.; Pieribone, V.; Hokfelt, T. Distributions of mRNAs for [204] Agnati, L.F.; Ferre, S.; Lluis, C.; Franco, R.; Fuxe, K. Molecular alpha-2 adrenergic receptor subtypes in rat brain: an in situ mechanisms and therapeutical implications of intramembrane hybridization study. J. Comp. Neurol., 1993, 328, 575-594. receptor/receptor interactions among heptahelical receptors with [185] Holmberg, M.; Scheinin, M.; Kurose, H.; Miettinen, R. Adrenergic examples from the striatopallidal GABA neurons. Pharmacol. Rev., alpha2C-receptors reside in rat striatal GABAergic projection neurons: 2003, 55, 509-550. comparison of radioligand binding and immunohistochemistry. [205] Cabello, N.; Gandia, J.; Bertarelli, D.C.; Watanabe, M.; Lluis, C.; Neuroscience, 1999, 93, 1323-1333. Franco, R.; Ferré, S.; Luján, R.; Ciruela, F. Metabotropic glutamate type [186] Alachkar, A.; Brotchie, J.; Jones, O.T. alpha2-Adrenoceptor-mediated 5, dopamine D2 and adenosine A2a receptors form higher-order modulation of the release of GABA and noradrenaline in the rat oligomers in living cells. J. Neurochem., 2009, 109, 1497-1507. substantia nigra pars reticulata. Neurosci. Lett., 2006, 395, 138-142. [206] Diaz-Cabiale, Z.; Hurd, Y.; Guidolin, D.; Finnman, U.B.; Zoli, M.; [187] Berretta, N.; Bernardi, G.; Mercuri, N.B. Alpha(1)-adrenoceptor- Agnati, L.F.; Vanderhaeghen, J.J.; Fuxe, K.; Ferré, S. Adenosine A2A mediated excitation of substantia nigra pars reticulata neurons. agonist CGS 21680 decreases the affinity of dopamine D2 receptors for Neuroscience, 2000, 98, 599-604. dopamine in human striatum. Neuroreport, 2001, 12, 1831-1834. [188] Fox, S.H.; Henry, B.; Hill, M.P.; Peggs, D.; Crossman, A.R.; Brotchie, [207] Canals, M.; Marcellino, D.; Fanelli, F.; Ciruela, F.; de Benedetti, P.; J.M. Neural mechanisms underlying peak-dose dyskinesia induced by Goldberg, S.R.; Neve, K.; Fuxe, K.; Agnati, L.F.; Woods, A.S.; Ferré, levodopa and apomorphine are distinct: evidence from the effects of the S.; Lluis, C.; Bouvier, M.; Franco, R. Adenosine A2A-dopamine D2 alpha(2) adrenoceptor antagonist idazoxan. Mov. Disord., 2001, 16, receptor-receptor heteromerization: qualitative and quantitative 642-650. assessment by fluorescence and bioluminescence energy transfer. J. [189] Buck, K.; Ferger, B. Comparison of intrastriatal administration of Biol. Chem., 2003, 278, 46741-46749. noradrenaline and l-DOPA on dyskinetic movements: a bilateral reverse [208] Morelli, M.; Pinna, A.; Wardas, J.; Di Chiara, G. Adenosine A2 in vivo microdialysis study in 6-hydroxydopamine-lesioned rats. receptors stimulate c-fos expression in striatal neurons of 6- Neuroscience, 2009, 159, 16-20. hydroxydopamine-lesioned rats. Neuroscience, 1995, 67, 49-55. [190] Gomez-Mancilla, B.; Bedard, P.J. Effect of nondopaminergic drugs on [209] Tronci, E.; Simola, N.; Carta, A.R.; De Luca, M.A.; Morelli, M. L-dopa-induced dyskinesias in MPTP-treated monkeys. Clin. Potentiation of -mediated responses in caffeine-sensitized Neuropharmacol., 1993, 16, 418-427. rats involves modifications in A2A receptors and zif-268 mRNAs in [191] Henry, B.; Fox, S.H.; Peggs, D.; Crossman, A.R.; Brotchie, J.M. The striatal neurons. J. Neurochem., 2006, 98, 1078-1089. alpha2-adrenergic receptor antagonist idazoxan reduces dyskinesia and [210] Shiozaki, S.; Ichikawa, S.; Nakamura, J.; Kitamura, S.; Yamada, K.; enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned Kuwana, Y. Actions of adenosine A2A receptor antagonist KW-6002 primate model of Parkinson's disease. Mov. Disord., 1999, 14, 744-753. on drug-induced catalepsy and hypokinesia caused by reserpine or [192] Savola, J.M.; Hill, M.; Engstrom, M.; Merivuori, H.; Wurster, S.; MPTP. Psychopharmacology (Berl.), 1999, 147, 90-95. McGuire, S.G.; Fox, S.H.; Crossman, A.R.; Brotchie, J.M. Fipamezole [211] Hauber, W.; Neuscheler, P.; Nagel, J.; Muller, C.E. Catalepsy induced (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces by a blockade of dopamine D1 or D2 receptors was reversed by a levodopa-induced dyskinesia in the MPTP-lesioned primate model of concomitant blockade of adenosine A(2A) receptors in the caudate- Parkinson's disease. Mov. Disord., 2003, 18, 872-883. putamen of rats. Eur. J. Neurosci., 2001, 14, 1287-1293. [193] Buck, K.; Voehringer, P.; Ferger, B. The alpha(2) adrenoceptor [212] Kanda, T.; Jackson, M.J.; Smith, L.A.; Pearce, R.K.; Nakamura, J.; antagonist idazoxan alleviates L-DOPA-induced dyskinesia by Kase, H.; Kuwana, Y.; Jenner, P. Adenosine A2A antagonist: a novel reduction of striatal dopamine levels: an in vivo microdialysis study in antiparkinsonian agent that does not provoke dyskinesia in parkinsonian 6-hydroxydopamine-lesioned rats. J. Neurochem., 2010, 112, 444-452. monkeys. Ann. Neurol., 1998, 43, 507-513. [194] Buck, K.; Ferger, B. The selective alpha1 adrenoceptor antagonist [213] Grondin, R.; Bedard, P.J.; Hadj Tahar, A.; Gregoire, L.; Mori, A.; Kase, HEAT reduces L-DOPA-induced dyskinesia in a rat model of H. Antiparkinsonian effect of a new selective adenosine A2A receptor Parkinson's disease. Synapse, 2010, 64, 117-126. antagonist in MPTP-treated monkeys. Neurology, 1999, 52, 1673-1677. [195] Visanji, N.P.; Fox, S.H.; Johnston, T.H.; Millan, M.J.; Brotchie, J.M. [214] Ochi, M.; Shiozaki, S.; Kase, H. Adenosine A(2A) receptor-mediated Alpha1-adrenoceptors mediate dihydroxyphenylalanine-induced modulation of GABA and glutamate release in the output regions of the activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned basal ganglia in a rodent model of Parkinson's disease. Neuroscience, macaques. J. Pharmacol. Exp. Ther., 2009, 328, 276-283. 2004, 127, 223-231. [196] Rascol, O.; Arnulf, I.; Peyro-Saint Paul, H.; Brefel-Courbon, C.; [215] Morelli, M.; Di Paolo, T.; Wardas, J.; Calon, F.; Xiao, D.; Vidailhet, M.; Thalamas, C.; Bonnet, A.M.; Descombes, S.; Bejjani, B.; Schwarzschild, M.A. Role of adenosine A2A receptors in parkinsonian Fabre, N.; Montastruc, J.L.; Agid, Y. Idazoxan, an alpha-2 antagonist, motor impairment and l-DOPA-induced motor complications. Prog. and L-DOPA-induced dyskinesias in patients with Parkinson's disease. Neurobiol., 2007, 83, 293-309. Mov. Disord., 2001, 16, 708-713. [216] Calon, F.; Dridi, M.; Hornykiewicz, O.; Bedard, P.J.; Rajput, A.H.; Di [197] Jenner, P.; Mori, A.; Hauser, R.; Morelli, M.; Fredholm, B.B.; Chen, Paolo, T. Increased adenosine A2A receptors in the brain of Parkinson's J.F. Adenosine, adenosine A 2A antagonists, and Parkinson's disease. disease patients with dyskinesias. Brain, 2004, 127, 1075-1084. Parkinsonism Relat. Disord., 2009, 15, 406-413. [217] Bibbiani, F.; Oh, J.D.; Petzer, J.P.; Castagnoli, N., Jr.; Chen, J.F.; [198] Morelli, M.; Carta, A.R.; Jenner, P. Adenosine A2A receptors and Schwarzschild, M.A.; Chase, T.N. A2A antagonist prevents dopamine Parkinson's disease. Handb. Exp. Pharmacol., 2009, 589-615. agonist-induced motor complications in animal models of Parkinson's [199] Augood, S.J.; Emson, P.C. Adenosine A2a receptor mRNA is disease. Exp. Neurol., 2003, 184, 285-294. expressed by enkephalin cells but not by somatostatin cells in rat [218] Xiao, D.; Bastia, E.; Xu, Y.H.; Benn, C.L.; Cha, J.H.; Peterson, T.S.; striatum: a co-expression study. Brain Res. Mol. Brain Res., 1994, 22, Chen, J.F.; Schwarzschild, M.A. Forebrain adenosine A2A receptors 204-210. contribute to L-3,4-dihydroxyphenylalanine-induced dyskinesia in [200] Schiffmann, S.N.; Libert, F.; Vassart, G.; Vanderhaeghen, J.J. hemiparkinsonian mice. J. Neurosci., 2006, 26, 13548-13555. Distribution of adenosine A2 receptor mRNA in the human brain. [219] Lundblad, M.; Vaudano, E.; Cenci, M.A. Cellular and behavioural Neurosci. Lett., 1991, 130, 177-181. effects of the adenosine A2a receptor antagonist KW-6002 in a rat [201] Hettinger, B.D.; Lee, A.; Linden, J.; Rosin, D.L. Ultrastructural model of l-DOPA-induced dyskinesia. J. Neurochem., 2003, 84, 1398- localization of adenosine A2A receptors suggests multiple cellular sites 1410. for modulation of GABAergic neurons in rat striatum. J. Comp. [220] Kanda, T.; Jackson, M.J.; Smith, L.A.; Pearce, R.K.; Nakamura, J.; Neurol., 2001, 431, 331-346. Kase, H.; Kuwana, Y.; Jenner, P. Combined use of the adenosine [202] Ferre, S.; Karcz-Kubicha, M.; Hope, B.T.; Popoli, P.; Burgueno, J.; A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 Gutiérrez, M.A.; Casadó, V.; Fuxe, K.; Goldberg, S.R.; Lluis, C.; dopamine agonists increases antiparkinsonian activity but not Franco, R.; Ciruela, F. Synergistic interaction between adenosine A2A dyskinesia in MPTP-treated monkeys. Exp. Neurol., 2000, 162, 321- and glutamate mGlu5 receptors: implications for striatal neuronal 327. function. Proc. Natl. Acad. Sci. USA, 2002, 99, 11940-11945. [221] Bara-Jimenez, W.; Sherzai, A.; Dimitrova, T.; Favit, A.; Bibbiani, F.; [203] Ferre, S.; Woods, A.S.; Navarro, G.; Aymerich, M.; Lluis, C.; Franco, Gillespie, M.; Morris, M.J.; Mouradian, M.M.; Chase, T.N. Adenosine R. Calcium-mediated modulation of the quaternary structure and A(2A) receptor antagonist treatment of Parkinson's disease. Neurology, function of adenosine A2A-dopamine D2 receptor heteromers. Curr. 2003, 61, 293-296. Opin. Pharmacol., 10, 67-72. 684 CNS & Neurological Disorders - Drug Targets, 2011, Vol. 10, No. 6 Cenci et al.

[222] Hauser, R.A.; Hubble, J.P.; Truong, D.D. Randomized trial of the [239] Miller, A.S.; Sanudo-Pena, M.C.; Walker, J.M. Ipsilateral turning adenosine A(2A) receptor antagonist istradefylline in advanced PD. behavior induced by unilateral microinjections of a cannabinoid into the Neurology, 2003, 61, 297-303. rat subthalamic nucleus. Brain Res., 1998, 793, 7-11. [223] Hauser, R.A.; Shulman, L.M.; Trugman, J.M.; Roberts, J.W.; Mori, A.; [240] Sanudo-Pena, M.C.; Walker, J.M. Role of the subthalamic nucleus in Ballerini, R.; Sussman, N.M.; Istradefylline 6002-US-013 Study Group. cannabinoid actions in the substantia nigra of the rat. J. Neurophysiol., Study of istradefylline in patients with Parkinson's disease on levodopa 1997, 77, 1635-1638. with motor fluctuations. Mov. Disord., 2008, 23, 2177-2185. [241] Sanudo-Pena, M.C.; Walker, J.M. Effects of intrapallidal cannabinoids [224] LeWitt, P.A.; Guttman, M.; Tetrud, J.W.; Tuite, P.J.; Mori, A.; Chaikin, on rotational behavior in rats: interactions with the dopaminergic P.; Sussman, N.M.; 6002-US-005 Study Group. Adenosine A2A system. Synapse, 1998, 28, 27-32. receptor antagonist istradefylline (KW-6002) reduces "off" time in [242] Brotchie, J.M. Nondopaminergic mechanisms in levodopa-induced Parkinson's disease: a double-blind, randomized, multicenter clinical dyskinesia. Mov. Disord., 2005, 20, 919-931. trial (6002-US-005). Ann. Neurol., 2008, 63, 295-302. [243] Morgese, M.G.; Cassano, T.; Gaetani, S.; Macheda, T.; Laconca, L.; [225] Pinna, A. Novel investigational adenosine A2A receptor antagonists for Dipasquale, P.; Ferraro, L.; Antonelli, T.; Cuomo, V.; Giuffrida, A. Parkinson's disease. Expert Opin. Investig. Drugs, 2009, 18, 1619-1631. Neurochemical changes in the striatum of dyskinetic rats after [226] Johansson, P.A.; Andersson, M.; Andersson, K.E.; Cenci, M.A. administration of the cannabinoid agonist WIN55,212-2. Neurochem. Alterations in cortical and basal ganglia levels of opioid receptor Int., 2009, 54, 56-64. binding in a rat model of l-DOPA-induced dyskinesia. Neurobiol. Dis., [244] Morgese, M.G.; Cassano, T.; Cuomo, V.; Giuffrida, A. Anti-dyskinetic 2001, 8, 220-239. effects of cannabinoids in a rat model of Parkinson's disease: role of [227] Aubert, I.; Guigoni, C.; Li, Q.; Dovero, S.; Bioulac, B.H.; Gross, C.E.; CB(1) and TRPV1 receptors. Exp. Neurol., 2007, 208, 110-119. Crossman, A.R.; Bloch, B.; Bezard, E. Enhanced preproenkephalin-B- [245] Fox, S.H.; Lang, A.E.; Brotchie, J.M. Translation of nondopaminergic derived opioid transmission in striatum and subthalamic nucleus treatments for levodopa-induced dyskinesia from MPTP-lesioned converges upon globus pallidus internalis in L-3,4- nonhuman primates to phase IIa clinical studies: keys to success and dihydroxyphenylalanine-induced dyskinesia. Biol. Psychiatry, 2007, 61, roads to failure. Mov. Disord., 2006, 21, 1578-1594. 836-844. [246] Bordia, T.; Campos, C.; Huang, L.; Quik, M. Continuous and [228] Piccini, P.; Weeks, R.A.; Brooks, D.J. Alterations in opioid receptor intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine binding in Parkinson's disease patients with levodopa-induced (L-DOPA)-induced dyskinesias in a rat model of Parkinson's disease. J. dyskinesias. Ann. Neurol., 1997, 42, 720-726. Pharmacol. Exp. Ther., 2008, 327, 239-247. [229] Calon, F.; Birdi, S.; Rajput, A.H.; Hornykiewicz, O.; Bedard, P.J.; Di [247] Quik, M.; Cox, H.; Parameswaran, N.; O'Leary, K.; Langston, J.W.; Di Paolo, T. Increase of preproenkephalin mRNA levels in the putamen of Monte, D. Nicotine reduces levodopa-induced dyskinesias in lesioned Parkinson disease patients with levodopa-induced dyskinesias. J. monkeys. Ann. Neurol., 2007, 62, 588-596. Neuropathol. Exp. Neurol., 2002, 61, 186-196. [248] Youdim, M.B.; Buccafusco, J.J. CNS Targets for multi-functional drugs [230] Henry, B.; Fox, S.H.; Crossman, A.R.; Brotchie, J.M. Mu- and delta- in the treatment of Alzheimer's and Parkinson's diseases. J. Neural opioid receptor antagonists reduce levodopa-induced dyskinesia in the Transm., 2005, 112, 519-537. MPTP-lesioned primate model of Parkinson's disease. Exp. Neurol., [249] Perez, X.A.; O'Leary, K.T.; Parameswaran, N.; McIntosh, J.M.; Quik, 2001, 171, 139-146. M. Prominent role of alpha3/alpha6beta2* nAChRs in regulating [231] Koprich, J.B.; Fox, S.H.; Johnston, T.H.; Goodman, A.; Le evoked dopamine release in primate putamen: effect of long-term Bourdonnec, B.; Dolle, R.E.; Dehaven, R.N.; Dehaven-Hudkins, D.L.; nicotine treatment. Mol. Pharmacol., 2009, 75, 938-946. Little, P.J.; Brotchie, J.M. The selective mu-opioid receptor antagonist [250] Huang, L.; Grady, S.R.; Quik, M. Nicotine Reduces L-Dopa-Induced adl5510 reduces levodopa-induced dyskinesia without affecting Dyskinesias by Acting at {beta}2 Nicotinic Receptors. J. Pharmacol. antiparkinsonian action in mptp-lesioned macaque model of Parkinson's Exp. Ther., 2011, epub ahead of print. disease. Mov. Disord., 26, 1225-1233. [251] Diener, H.F. Guidelines of the German Society for Neurology. 2008, [232] Samadi, P.; Gregoire, L.; Bedard, P.J. The opioid agonist morphine 4th edition. decreases the dyskinetic response to dopaminergic agents in [252] Lundblad, M.; Usiello, A.; Carta, M.; Hakansson, K.; Fisone, G.; Cenci, parkinsonian monkeys. Neurobiol. Dis., 2004, 16, 246-253. M.A. Pharmacological validation of a mouse model of l-DOPA- [233] Cox, H.; Togasaki, D.M.; Chen, L.; Langston, J.W.; Di Monte, D.A.; induced dyskinesia. Exp. Neurol., 2005, 194, 66-75. Quik, M. The selective kappa-opioid receptor agonist U50,488 reduces [253] Blanchet, P.J.; Konitsiotis, S.; Chase, T.N. Amantadine reduces L-dopa-induced dyskinesias but worsens parkinsonism in MPTP- levodopa-induced dyskinesias in parkinsonian monkeys. Mov. Disord., treated primates. Exp. Neurol., 2007, 205, 101-107. 1998, 13, 798-802. [234] van de Witte, S.V.; Groenewegen, H.J.; Drukarch, B.; Voorn, P. [254] Grégoire, L.; Samadi, P.; Graham, J.; Bédard, P.J.; Bartoszyk, G.D.; Di Dynorphin modulates dopamine D1-receptor mediated turning behavior Paolo, T. Low doses of sarizotan reduce dyskinesias and maintain in 6-hydroxydopamine-lesioned rats. Neurosci. Lett., 2000, 290, 37-40. antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys. [235] Voorn, P.; van de Witte, S.V.; Li, K.; Jonker, A.J. Dynorphin displaces Parkinsonism Relat. Disord., 2009, 15, 445-452. binding at the glycine site of the NMDA receptor in the rat striatum. [255] Jaunarajs, K.L.; Dupre, K.B.; Steiniger, A.; Klioueva, A.; Moore, A.; Neurosci. Lett., 2007, 415, 55-58. Kelly, C.; Bishop, C. Serotonin 1B receptor stimulation reduces D1 [236] Giuffrida, A.; Parsons, L.H.; Kerr, T.M.; Rodriguez de Fonseca, F.; receptor agonist-induced dyskinesia. Neuroreport, 2009, 20, 1265- Navarro, M.; Piomelli, D. Dopamine activation of endogenous 1269. cannabinoid signaling in dorsal striatum. Nat. Neurosci., 1999, 2, 358- [256] Gomez-Ramirez, J.; Johnston, T.H.; Visanji, N.P.; Fox, S.H.; Brotchie, 363. J.M. Histamine H3 receptor agonists reduce L-dopa-induced chorea, [237] Sanudo-Pena, M.C.; Patrick, S.L.; Patrick, R.L.; Walker, J.M. Effects of but not dystonia, in the MPTP-lesioned nonhuman primate model of intranigral cannabinoids on rotational behavior in rats: interactions with Parkinson's disease. Mov. Disord., 2006, 21, 839-846. the dopaminergic system. Neurosci. Lett., 1996, 206, 21-24. [257] Bordia, T.; Campos, C.; McIntosh, J.M.; Quik, M. Nicotinic receptor- [238] Sanudo-Pena, M.C.; Force, M.; Tsou, K.; Miller, A.S.; Walker, J.M. mediated reduction in L-dopa-induced dyskinesias may occur via Effects of intrastriatal cannabinoids on rotational behavior in rats: desensitization. J. Pharmacol. Exp. Ther., 2010, 333(3), 929-938. interactions with the dopaminergic system. Synapse, 1998, 30, 221-226.

Received: May 19, 2010 Revised: July 2, 2011 Accepted: July 5, 2011

PMID: 21838677