Advances in the pharmacological treatment of Parkinson's disease: targeting neurotransmitter systems

Review

Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems Lars Brichta, Paul Greengard, and Marc Flajolet Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA

For several decades, the dopamine precursor levodopa has been the primary therapy for Parkinson’s disease (PD). However, not all of the motor and non-motor features of PD can be attributed solely to dopaminergic dysfunction. Recent clinical and preclinical advances provide a basis for the identification of additional innovative therapeutic options to improve the management of the disease. Novel pharmacological strategies must be optimized for PD by: (i) targeting disturbances of the serotonergic, noradrenergic, glutamatergic, GABAergic, and cholinergic systems in addition to the dopaminergic system, and (ii) characterizing alterations in the levels of neurotransmitter receptors and transporters that are associated with the various manifestations of the disease. Introduction Parkinson’s disease (PD), the second most common neurodegenerative disorder of the brain, is primarily characterized by akinesia, rigidity, resting tremor, and postural instability. These motor signs are mainly due to progressive degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Importantly, PD is also associated with numerous debilitating non-motor features such as cognitive deficits ranging from memory impairment to dementia, emotional changes such as depression and anxiety, as well as sleep perturbations, sensation disturbances, autonomic dysfunction, and gastrointestinal symptoms [1–3]. Non-motor symptoms largely contribute to the reduced quality of life and disability associated with the disease [4–6]. The gold standard for symptomatic therapy of PD is a pharmacological regimen based on dopamine replacement with the pro-drug levodopa (L-DOPA) in combination with an inhibitor of its peripheral conversion to dopamine (carbidopa or benserazide). L-DOPA does not effectively relieve all of the features associated with PD. In particular, postural instability, tremor, and the majority of non-motor manifestations are less likely to respond to current therapy. Furthermore, long-term treatment with L-DOPA commonly leads to progressive loss of efficacy, the development of dyskinesias in a high percentage of patients within 5 years of therapy, and multiple non-motor manifestations [7–9]. Corresponding author: Brichta, L. ([email protected]). Keywords: Parkinson’s disease; glutamate; serotonin; acetylcholine; GABA; norepinephrine; dopamine; striatum; substantia nigra; basal ganglia. 0166-2236/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2013.06.003

Given the adverse effects and limitations of current therapeutic regimens, there is an urgent need for improved pharmacological options. Although there have been very limited clinical advancements for the pharmacological treatment of PD since the approval of L-DOPA more than 40 years ago, results from recent clinical and preclinical trials will provide a basis for new therapeutic avenues. This review highlights novel strategies that specifically target receptors or transporters of the major neurotransmitter systems of the brain to correct signaling abnormalities associated with PD or L-DOPA-induced dyskinesia (LID). We discuss the rationale of these efforts and identify areas requiring further investigation to develop suitable pharmacological treatment strategies and novel drug targets for more effective management of PD. Basis for limited success of clinical trials for PD PD is associated with a unique combination of the brain regions involved and complex changes in various modulatory pathways. As outlined below, these changes include specific alterations in the expression levels of neurotransmitter receptors and transporters that change over the course of the disease. Unfortunately, a significant fraction of past and current clinical trials involve test compounds that are not optimized to treat the signaling abnormalities specific to PD. Instead, many drug candidates were initially designed for the treatment of different disorders. Although some of these molecules may still prove useful in complementing existing pharmacological therapies, they do not necessarily represent innovative strategies nor are they maximally efficacious for treating a particular feature of PD. Several examples demonstrate these limitations. A large number of clinical trials for PD have been conducted or are currently in progress (1090 studies according to www.clinicaltrials.gov, July 2013). Table 1 lists the drugs in Phase III clinical trials. Safinamide is a drug that blocks sodium channels, antagonizes the release of glutamate, and inhibits monoamineoxidase B and the reuptake of dopamine. It was originally developed as an anticonvulsant and is currently undergoing clinical testing for various applications, including its ability to improve motor signs in patients with early PD as an adjunct to dopamine agonist therapy (Table 1) [10,11]. The cholinesterase inhibitors rivastigmine, donepezil, and galantamine, as well as the glutamatergic receptor antagonist memantine, are drugs approved for Trends in Neurosciences, September 2013, Vol. 36, No. 9

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Table 1. Compounds in Phase III clinical trials for PD registered with www.clinicaltrials.gov (January 2013) Mechanism of action

Comments

Motor signs Amantadine

NMDA receptor antagonist

BIA 9-1067 (Opicapone)

COMT inhibitor

Creatine Deferiprone IPX066 Istradefylline

Antioxidant? Iron chelator Extended release A2A receptor antagonist

KW6500 (Apomorphine)

Dopamine receptor agonist

Lisuride

Dopamine receptor agonist

Pramipexole

Dopamine receptor agonist

Preladenant Rasagiline

A2A receptor antagonist MAO-B inhibitor

Ropinirole

Dopamine receptor agonist

Rotigotine

Dopamine receptor agonist

Safinamide SYN-115 (Tozadenant)

MAO-B inhibitor A2A receptor antagonist

Evaluation of drug efficacy for the treatment of L-DOPA-induced dyskinesia and for therapy of gait abnormalities and freezing of gait Add-on to L-DOPA + carbidopa/benserazide in patients with wearing-off phenomenon Evaluation of ability to slow the progression of PD Test its ability to reduce iron overload in the brain L-DOPA/carbidopa formulation to reduce off-time Evaluation of drug efficacy to treat wearing-off signs associated with L-DOPA therapy in patients with PD Investigation of safety and efficacy of subcutaneous self-injections in PD patients with motor response complications during L-DOPA therapy Evaluation of efficacy of subcutaneous infusions in patients with advanced PD with motor fluctuations and off periods refractory to conventional treatment Determination of efficacy, safety, and tolerability of extended release formulation; evaluation of efficacy and safety of long-term treatment Evaluation of drug efficacy for treatment of wearing-off signs observed with L-DOPA Evaluation of effect on motor fluctuations in PD patients treated with L-DOPA; disease-modifying effect was investigated previously Evaluation of extended drug release tablets and transdermal systems; investigation of efficacy as add-on therapy in PD patients not well controlled with L-DOPA Evaluation of transdermal patches to treat motor signs of PD; investigation of efficacy to treat motor signs in PD patients with gastroparesis Evaluation as adjunct to dopamine agonist therapy or to L-DOPA therapy Evaluation of drug efficacy for the treatment of wearing-off signs observed with LDOPA

Depression Paroxetine

SSRI

S-Adenosyl-methionine Venlafaxine

Methyl donor SNRI

Cognition, dementia and psychosis Cholinesterase inhibitor Donepezil

Evaluation of impact on PD-related depression and motor features (tremor, stiffness, slowness, balance) Evaluation of impact on depression associated with PD Evaluation of impact on PD-related depression and motor features (tremor, stiffness, slowness, balance) Evaluation of effect on cognitive function, neuropsychiatric burden, and functional ability in PD patients with mild dementia Efficacy for treatment of psychosis associated with PD Effects on vigilance and cognitive performance in patients with PD Long-term effect on worsening of motor signs in patients with PD and dementia; efficacy for treatment of apathy without dementia in patients with PD

Pimavanserin Piribedil Rivastigmine

5-HT2A inverse agonist Dopamine receptor agonist Cholinesterase inhibitor

Sleep and sleepiness BF2.649 (Pitolisant) Caffeine Eszopiclone Rotigotine

H3 receptor inverse agonist Non-selective A2A antagonist GABAA receptor agonist Dopamine receptor agonist

Efficacy for therapy of excessive daytime sleepiness in patients with PD Evaluation of drug effect on excessive daytime sleepiness and motor features Treatment of insomnia in patients with PD Evaluation of drug efficacy to treat sleep disorders and motor signs in patients with PD

Pain OXN (oxycodone/naloxone)

Opioid receptor modulator

Analgesic efficacy of prolonged release tablets in PD patients with chronic severe pain

the treatment of Alzheimer’s disease (AD)-related dementia. These compounds have been investigated for the treatment of dementia in PD [12–17]. Although rivastigmine is considered clinically useful, evidence of the efficacy of the other drugs tested is currently insufficient [18]. The limited success of these trials may be partly attributable to the fact that different signaling abnormalities are likely to underlie the dementia in AD and in PD. Similarly, the etiology of depression in PD is likely to be distinct from that of major depressive disorder, and drugs that are most commonly prescribed for major depressive disorder are not the most efficacious option for the therapy of depression in patients with PD (see the section on 544

serotonin for details). These examples emphasize the need for therapeutic strategies that are specific to PD. To date, the relevant signaling alterations associated with PD have only been partly explored and compounds targeting them have the potential to be more effective and more potent with a more favorable side effect profile than current options. The recent progress in this field is discussed below. Neuromodulatory projection systems Dopamine The preferential degeneration of SN DA neurons is a hallmark of PD. The consequent loss of dopamine that

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Cortex

D1 D2 D4 D5

Dorsal D1 D2 striatum D5 GP D4

Hypothalamus D1 D2 D4 D5

D1 D2 D4 D5

Hip poc am pus

Nucl. acc. D1 D2 D3 D5

Dopamine receptors: (G protein-coupled) D1-like: D1, D5 D2-like: D2, D3, D4

SN D2 D3 D5

VTA D2 D3 D5

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Figure 1. Dopaminergic (DA) projection pattern and distribution of dopamine receptors in the brain. DA neurons in the substantia nigra (SN) and ventral tegmental area (VTA) represent the two largest DA cell clusters in the mammalian brain. Axons of DA neurons in the SN project mainly to the dorsal striatum (nigrostriatal system), with a small percentage innervating specific areas of the cortex and nucleus accumbens. Some collaterals from projections to the dorsal striatum also innervate extrastriatal nuclei, including the globus pallidus (GP). Whereas only a small number of VTA neurons project to the dorsal striatum, DA VTA neurons primarily innervate the nucleus accumbens and several cortical areas (mesolimbic and mesocortical DA systems). DA VTA neurons also project to additional structures including the hippocampus and hypothalamus. Dopamine receptors are widely expressed in the human brain [20,21]. D1 mRNA expression levels are highest in the dorsal striatum and nucleus accumbens, but are also found in the cortex and at lower levels in the hippocampus, thalamus, and hypothalamus. Similar to D1, the D2 receptor is highly expressed in spiny projection neurons (SPNs) in the dorsal and ventral striatum. D2 mRNA is also expressed in cortex, hippocampus and hypothalamus. Moreover, DA neurons of the SN and VTA express D2 autoreceptors. D3 is present in particular in the nucleus accumbens, with only very low levels in the dorsal striatum, hippocampus, and cortex. Low levels of D3 autoreceptors have been detected in SN and VTA neurons. However, D2 is much more abundant in these neurons than D3 is. Of note, D3 receptors have also been detected in the terminals of striatal neurons that project to the GP. D4 shows the lowest expression levels among all DA receptors in the basal ganglia. Brain regions with detectable levels of D4 mRNA include the cortex, hippocampus, and hypothalamus. Moreover, GABAergic neurons in the GP express D4. Similar to the D4 receptor, D5 is expressed at much lower levels than D1 and D2. The D5 receptor has been detected in the cortex, dorsal and ventral striatum, hypothalamus, and hippocampus. In the dorsal striatum, D5 is localized in SPNs and in cholinergic interneurons. Low levels of D5 have also been detected in the SN. Abbreviations: Nucl. acc., nucleus accumbens. Autoreceptors are underlined.

occurs in the dorsal striatum also extends to additional regions of the basal ganglia. Therefore, altered dopamine signaling in various basal ganglia structures may contribute to manifestation of the motor features observed in PD. In support of this hypothesis, postmortem dopamine levels are extensively reduced in the globus pallidus, with a possible correlation between the pattern of dopamine depletion and the presence of tremor [19]. Moreover, the degeneration of ventral tegmental DA projections to limbic brain areas is likely to be involved in the etiology of some of the non-motor features, including depression. L-DOPA nonspecifically increases the concentration of dopamine at dopamine receptors in the brain, and thus efficiently relieves some of the cardinal signs of PD. Targeting of dopamine receptors for therapy is greatly facilitated by the considerable amount of knowledge accumulated over the years regarding the expression of the five

dopamine receptors in the brain, which is summarized in the map presented in Figure 1. In some cases, dopamine receptor agonists are used for symptomatic treatment of PD. Most agonists either bind to both D2 and D1 receptors, or interact with the D2 receptor without affecting D1. Dopamine receptor stimulation in the dorsal striatum is the primary mechanism by which these drugs partly alleviate the motor features that are associated with PD. The D3 receptor is predominantly expressed by neurons in limbic regions of the brain including the ventral striatum (Figure 1), and positron emission tomography (PET) imaging suggests that D3 receptor levels are downregulated in the ventral striatum in PD patients before drug treatment [22]. Therefore, D3 appears to be a promising target for the treatment of non-motor symptoms associated with PD. The results from several clinical studies support this view. Pramipexole is a non-ergot dopamine receptor agonist with 545

Review a higher affinity for D3 than for D2 [23]. In addition to improving the motor signs of PD via D2, pramipexole also directly alleviates PD-related depression [24]. The latter effect is likely due to D3 agonism in the nucleus accumbens. However, autoradiography studies in aged human brain were able to detect the D3 receptor in additional brain regions including the thalamus [25], and PET imaging data obtained in healthy subjects suggest that pramipexole is able to bind to these sites [26]. Thus, it is possible that several components of the limbic system mediate the antidepressant effect of pramipexole. A clinical study with the mixed D3/D2 agonist ropinirole also suggested an improvement in depression in patients with PD [27]. These data clearly emphasize that the dysfunction of the DA system in PD contributes to the pathogenesis of PD-related depression, and that pharmacological agents targeting in particular the D3 receptor appear to be a successful treatment approach. Interestingly, increasing evidence supports a contributory role of the D1 receptor in the development of LID. In dyskinetic parkinsonian non-human primates, D1 was enriched in the plasma membrane and the cytoplasm of direct spiny projection neurons (SPNs) in the striatum, resulting in enhanced D1 receptor-mediated signal transmission and extensive activation of downstream signaling pathways [28,29]. Studies are warranted to confirm this observation in dyskinetic PD patients and to further evaluate these D1-related changes as potential therapeutic targets for the treatment of LID. Serotonin In patients with early or advanced PD, reduced [11C]DASB binding to serotonin transporter, a marker for serotonergic (5-HT) neurons, was measured in various brain regions including the dorsal striatum, the midbrain, and several cortical regions [30,31]. Levels of serotonin, its metabolite 5-hydroxyindoleacetic acid, serotonin transporter, and tryptophan hydroxylase are reduced in striatal tissue from PD patients compared to controls [32]. On the basis of the data currently available, it is reasonable to postulate that serotonin depletion is involved in, but not the sole trigger of, PD-related depression. Depression is very common in patients diagnosed with PD and can precede the onset of motor manifestations by several years [33,34]. The selective serotonin re-uptake inhibitor (SSRI) paroxetine and the serotonin/norepinephrine re-uptake inhibitor (SNRI) venlafaxine improve PD-related depression compared to placebo in some patients, indicating the efficacy of drugs that inhibit presynaptic re-uptake of serotonin via the serotonin transporter in a subgroup of individuals with PD (Table 1) [35]. However, not all patients respond to SSRI treatment. These data suggest that PD-related depression is not fully attributable to perturbations in serotonin signaling. The success of pramipexole in the treatment of PDrelated depression emphasizes the DA component of this feature (see the previous section). Moreover, PET imaging of PD patients diagnosed with depression showed lower [11C]RTI-32 binding to the dopamine and noradrenaline transporters in limbic brain regions compared to PD patients without depression [36]. These results indicate more severe loss of DA and noradrenergic (NA) innervations 546

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in discrete areas of the brain, establishing a neuropathological basis for the involvement of both dopamine and noradrenaline in the etiology of mood disturbances associated with PD. Several clinical trials have facilitated the translation of these findings into promising treatment strategies. A study in PD patients with depression demonstrated that nortriptyline, a tricyclic inhibitor of the re-uptake of both serotonin and norepinephrine, is superior to the SSRI paroxetine [37]. In line with these data, a separate investigation in individuals with PD and depression revealed that the use of desipramine, another tricyclic antidepressant, resulted in a more intense short-term effect than the SSRI citalopram [38]. It can therefore be concluded that drugs targeting both the serotonin and noradrenaline transporters seem to be more suitable for the treatment of PD-related depression than compounds targeting the serotonin transporter alone. It would be of interest to study how pramipexole compares to tricyclic antidepressants and if the combined use of these drugs would result in a synergistic effect. The novel selective 5-HT2A inverse agonist pimavanserin (ACP103) is currently undergoing clinical testing for PD-related psychosis, a common non-motor feature often associated with dopamine replacement therapy. A pilot trial indicated that the drug may improve psychotic symptoms in individuals with PD [39]. 5-HT2A is widely expressed in the normal CNS (Figure 2), but a PET pilot study with the selective 5-HT2A ligand setoperone-F18 indicated that receptor levels are increased in several cortical regions in L-DOPA-treated PD patients with visual hallucinations compared to those without these symptoms [43]. Preliminary results obtained from postmortem tissue point to cortex region-specific upregulation of 5-HT2A in PD patients with visual hallucinations compared to those without hallucinations [44]. It is possible that both the receptor selectivity of pimavanserin and a region-specific increase in 5-HT2A receptor levels lead to more concerted action of the drug, thus minimizing adverse events. Evidence supporting the involvement of the 5-HT system in the pathogenesis of LID and efforts to identify antidyskinetic compounds that target serotonin receptors or the serotonin transporter have been summarized recently [41]. 5-HT1A agonism and 5-HT2A antagonism are considered promising strategies for alleviating LID. However, past clinical trials have demonstrated only limited success, mainly owing to exacerbation of the motor signs associated with PD. This can be explained by the widespread expression of serotonin receptors in the brain and their involvement in many different signaling circuits (Figure 2). An interesting new approach is the development of compounds that specifically interfere with the signaling of a subset of 5-HT1A or 5-HT2A receptors in distinct brain regions [45]. Norepinephrine Degeneration of NA neurons in the locus coeruleus (LC) and deficits in norepinephrine (NE) are common findings in PD, and abnormal NA signaling is likely to contribute to the development of mood changes associated with the disease (see the previous section). A link between NA pathology and the postural instability and gait abnormalities observed in PD was also postulated [46]. These motor

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Cortex 2A 2C 5

7 Dorsal striatum

Nucl. acc. 1B 2C 1D 4 2A 6

1B 1D 1E 2A

2C 3 4 6

Serotonin receptors:

Hip poc am pus

1A 1B 1E

[2C] SN VTA [2C]

1A 2A 1B 2C 3 6 7

G protein-coupled: 5-HT1A, 1B, 1D, 1E, 1F 5-HT2A, 2C 5-HT4 5-HT6 5-HT5 5-HT7 Ligand-gated ion channel: 5-HT3

1A RN 1B 1D

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Figure 2. Raphe nuclei (RN) and distribution of serotonin receptors in the brain. Dorsal RN innervate several regions of the basal ganglia, including the striatum, ventral tegmental area (VTA), substantia nigra (SN) pars reticulata, and to a lesser extent SN pars compacta. Moreover, serotonergic (5-HT) neurons in the brainstem project to limbic brain areas, including the cortex and hippocampus. 5-HT neurons innervate both dopaminergic (DA) neuronal cell bodies of the SN and the region of their terminal projections in the striatum. The anatomical interaction of the 5-HT system with DA components of the basal ganglia facilitates functional modulation of DA neurotransmission by serotonin in the normal, non-parkinsonian brain [40]. 5-HT receptors are classified into seven families that comprise at least 14 different receptor subtypes. For most 5-HT receptors, expression has been described in the human brain [41,42]. Receptor autoradiography studies revealed a high density of postsynaptic 5-HT1A binding sites in limbic areas, including the hippocampus and cortex. Presynaptic 5-HT1A receptors were detected on RN cell bodies and dendrites. 5-HT1B mRNA levels are high in the human dorsal striatum, nucleus accumbens, cortex, and RN. Lower levels were measured in the hippocampus. In situ hybridization analyses in rat brain mapped low 5-HT1D mRNA expression levels to the dorsal striatum, nucleus accumbens, and RN. 5-HT1B and 5-HT1D receptors are mostly located in the nerve terminals of neurons that project to other brain regions. Although the SN and globus pallidus (GP) display binding sites for 5-HT1B and 1D, mRNA was not detected in these two regions. Both receptors also serve as autoreceptors on RN neurons. 5-HT1E binding sites and mRNA were mapped to the human cortex and dorsal striatum. The expression of 5-HT1F receptor is very low. 5-HT2A mRNA and protein are highly abundant in the cortex, dorsal striatum, nucleus accumbens, and hippocampus. 5-HT2B mRNA and protein levels are very low in hippocampus and cortex. No signal was detected in basal ganglia. 5-HT2C binding sites and mRNA were detected in the dorsal striatum, nucleus accumbens, cortex, and hippocampus. 5-HT2C mRNA expression in DA neurons of the SN and VTA was demonstrated in some studies. However, those findings are controversial. In humans, 5-HT3 receptor binding sites are highly abundant in spiny projection neurons (SPNs) of the dorsal striatum and in the hippocampus, with a lower signal detected in the cortex. 5-HT4 mRNA and binding sites were detected in striatal SPNs. 5-HT4 binding sites in the GP and SN are derived from striatal projections. 5-HT5 mRNA was mainly detected in the cortex. 5-HT6 mRNA and protein are present in SPNs in the dorsal striatum and nucleus accumbens, as well as in the hippocampus. In rodents, 5-HT7 mRNA and binding sites are highly abundant in the hippocampus, with lower levels measured in the cortex. Abbreviations: Nucl. acc., nucleus accumbens. Autoreceptors are underlined.

manifestations are often resistant to L-DOPA therapy, so the involvement of non-DA neurotransmitter systems is likely. In support of this hypothesis, methylphenidate, a compound that inhibits dopamine and NE re-uptake via blockade of presynaptic transporters, was able to improve freezing of gait in patients with advanced PD who received deep brain stimulation [47]. Although these findings may open a new therapeutic strategy for treating gait abnormalities, preclinical and clinical trials have yet to demonstrate a direct connection between NA pathology and gait and postural abnormalities in PD. Once the neuropathological basis is established, the well-characterized expression pattern of adrenoceptors in basal ganglia and limbic regions of the normal brain may provide a starting point for the identification of suitable drug targets (Figure 3).

The NA system may also play a role in the development of LID. A Phase II trial with fipamezole, a selective a2 receptor antagonist, demonstrated that the drug improves LID features in PD patients [53]. The exact mechanism of action is not entirely clear. a2 antagonists bind to presynaptic a2 receptors (Figure 3), thereby stimulating NA activity. Conversely, antagonism of NE at postsynaptic adrenoceptors is another possible explanation for the antidyskinetic effect of fipamezole, and because a2 receptors are expressed in several brain nuclei in addition to the LC (Figure 3), fipamezole may work at these sites. Moreover, it remains to be elucidated if a2 receptor levels in patients with LID differ from the levels measured in subjects without LID, which may add yet another layer of complexity. 547

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Cortex

α1 α2 Striatum β1 β2

Hypothalamus α1 α2 β1 β2

Adrenergic receptors: (G protein-coupled)

Hip poc am pus

β1 β2

α1 α2

β1 β2

SN α1 β1 LC α2

α1A, α1B, α1D α2A, α2B, α2C β1, β2, β3

Cerebellum α1 α2 β1 β2

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Figure 3. Noradrenergic (NA) projections and expression pattern of norepinephrine (NE) receptors in the brain. The locus coeruleus (LC) in the pons is the main NA nucleus in the mammalian brain. NA neurons project to multiple regions of the basal ganglia and the limbic system including dopaminergic (DA) neurons of the substantia nigra (SN) and the ventral tegmental area (VTA), the striatum, neocortex, hippocampus, hypothalamus, and cerebellum. Besides NE, the LC produces various additional neuromodulators, including enkephalin, brain-derived neurotrophic factor, neuropeptide, and galanin. Similar to DA neurons in the SN, cells of the LC are pigmented due to the presence of neuromelanin. Adrenoceptors are subdivided into three major groups. The different receptors are characterized by distinct expression patterns in the brain as demonstrated by various autoradiographic studies. In human postmortem tissue, abundant levels of a1, a2, b1, and b2 receptors were detected in the cortex, hippocampus, hypothalamus, and cerebellum [48–51]. In the striatum, b1 and b2 receptors are most abundant, whereas only very low signals were measured for a1 and a2. Expression studies of adrenoceptors in human SN suggest the presence of a1 and b1 receptors in this brain region. By contrast, very low signals were obtained for a2 and b2. a2 receptors are also located on NA LC neurons, where they function as autoreceptors. Moreover, very low levels of b3 mRNA were detected in adult cortex, striatum, and SN [52]. Autoreceptors are underlined.

Classical neurotransmitter systems Glutamate The effects of glutamate are transmitted through ionotropic glutamate receptors (iGluRs) that are involved in fast synaptic transmission and metabotropic glutmate receptors (mGluRs) that mediate slow synaptic transmission [54]. mGluRs and iGluRs are widely expressed in various brain regions, including basal ganglia (Figure 4). Several lines of evidence indicate that the glutamatergic system contributes to the development of LID, although the molecular mechanisms underlying these observations are not completely understood. Binding studies in human postmortem tissue revealed that the levels of the NR1/ NR2B NMDA receptor, the AMPA receptor, and mGluR5 are increased in the putamen of patients with LID compared to those without LID [56,57]. Data from a PET study using [11C]CNS 5161, a marker for activated NMDA receptors, suggest that L-DOPA administration leads to elevated NMDA receptor activity in the caudate, putamen, and precentral cortex in PD patients with LID, but not in those without LID [58]. These findings support the hypothesis of enhanced glutamatergic neurotransmission in LID, and 548

provide several targets for therapeutic intervention. Amantadine, a drug sometimes used for treatment of akinesia and rigidity in early PD, is efficacious in improving the signs of LID [59]. It is believed that this effect is mediated via antagonism at NMDA receptors. However, amantadine is not selective for NMDA antagonism and also has affinity for other receptors, including the nicotinic receptor [60]. A pilot trial of the NR2B subunit-selective NMDA antagonist CP101,606 demonstrated that the drug improves the signs of dyskinesia [61]. However, severe adverse effects observed in humans, such as cognitive impairment, which can likely be explained by widespread expression of NMDA receptors in various brain regions, limit the use of NMDA antagonists [61]. Of note, amantadine and memantine, another NMDA antagonist, are being clinically tested for gait abnormalities in a small number of individuals with PD (Table 1 and www.clinicaltrials.gov). These investigations are based on the hypothesis that glutamatergic projections derived from the subthalamic nucleus (STN) cause hyperactivation of neurons in the pedunculopontine nucleus (PPN) in PD. These neurons are involved in the control of posture and

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Cortex 1,5

Striatum 2,3

1,5

• SPN+ • interneuron+

4,7

Thal.

GP 1,4,5,7

SN 1,4,5

STN 2,3,7

1,5

Metabotropic (mGluR): (G protein-coupled) Group I: 1,5 Group II: 2,3 Group III: 4,6,7,8 Ionotropic: NMDA AMPA

2,3,7

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Figure 4. The glutamatergic system and expression pattern of metabotropic glutamate receptors in the brain. Eight different metabotropic glutamate receptors (mGluR1–8) are divided into three groups: group I (mGluR1 and 5), group II (mGluR2 and 3), and group III (mGluR4, 6, 7, and 8). Receptors from all groups are expressed in the basal ganglia, where they play a crucial role under physiological conditions and in various disease states [55]. The striatum is the primary input nucleus in the basal ganglia. Besides dense innervation from dopaminergic (DA) substantia nigra (SN) neurons, the striatum receives excitatory afferents from the glutamatergic neurons in the cerebral cortex, the thalamus, and the amygdala. The striatum then modulates signaling in other brain regions through the basal ganglia output nuclei, the internal part of the globus pallidus (GPi) and the SN pars reticulata. The GABAergic output nuclei project to the thalamus, which innervates the cortex, completing the cortico–basal ganglia– thalamo–cortical circuit. The only nucleus in the basal ganglia that produces glutamate is the subthalamic nucleus (STN). The STN is involved in neurotransmission via the indirect pathway. The indirect striatopallidal pathway starts with spiny projection neurons (SPNs) that express dopamine receptor D2. These SPNs send axonal projections to the external globus pallidus (GPe), which then projects to the STN. The STN sends excitatory projections to the GPi, which innervates the thalamus. By contrast, the direct striatonigral pathway includes SPNs that highly express dopamine receptor D1 and project directly to the basal ganglia output nuclei. The direct and indirect pathways are differentially modulated by dopamine to fine tune movement. Whereas SPNs expressing D1 are excited by DA input from the SN, SPNs carrying D2 are inhibited by dopamine. The net effect of dopamine results in facilitation of movement. Abbreviations: GP, globus pallidus; Thal, thalamus. Pre-synaptic receptor subtypes are shown on the arrows; postsynaptic receptor subtypes are shown within the brain structures.

gait [62]. As outlined above, strategies targeting NMDA receptors are likely to result in limited success. Characterization of all the glutamate receptors expressed by relevant neurons in the PPN may lead to identification of a more promising target for therapy of gait disorders associated with PD. Because of their more specific expression pattern, modulation of mGluRs might represent a more promising approach than targeting iGluRs. mGluRs are located pre- and/or postsynaptically and are potentially able to mediate excitatory as well as inhibitory effects. mGluR5, a group I mGluR, is expressed throughout the basal ganglia, with highest levels observed in the striatum and STN (Figure 4). In two short-term studies with small sample sizes, the selective mGluR5 antagonist AFQ056 had an antidyskinetic effect in patients with moderate or severe LID [63]. The increased levels of mGluR5 in the putamen of dyskinetic patients may provide a direct explanation for

the improvement of LID induced by AFQ056 [57]. Another negative allosteric modulator of mGluR5, ADX48621, is currently being tested for treatment of LID in a Phase II trial (www.clinicaltrials.gov identifier NCT01336088). Moreover, numerous preclinical investigations are being carried out with several different positive allosteric modulators of mGluR4. These efforts have been reviewed in detail recently [64]. In rodent models of PD, selective activation of mGluR4 mediates antiparkinsonian and antidyskinetic effects, establishing mGluR4 as an exciting novel therapeutic target for drug development. GABA GABA signaling occurs via ionotropic GABAA and metabotropic GABAB receptors, which are expressed in all human basal ganglia structures. GABAA receptors in the mammalian brain contain combinations of a and b subunits plus one or more of the g, d, or e subunit types. In the striatum, 549

Review the two different types of GABAergic SPNs express dopamine receptors and give rise to the direct and the indirect signaling pathways [65]. PD patients have decreased DA input. Therefore, SPNs are affected by postsynaptic changes, resulting in an altered activity pattern for both pathways. This signaling alteration changes the output of the basal ganglia, causing some of the typical motor features seen in PD patients, including stiffness and bradykinesia. GABAergic neurotransmission itself is altered in PD. Binding studies in postmortem tissue indicate that LID is associated with increased levels of GABAA receptors in the internal globus pallidus, and that the presence of wearingoff signs of L-DOPA correlates with increased GABAA levels in the putamen [66]. The same study suggests a decreased density of GABAB receptors in the putamen and in the external globus pallidus in PD patients compared to controls. The description of these region-specific receptor alterations is interesting. However, follow-up studies are required to extend these findings to the development of therapeutic strategies. These investigations should identify which neuronal cell types are involved. Moreover, because GABAA receptors contain various combinations of distinct subunits, elucidation of the subunit composition of GABAA receptors in affected brain regions is crucial for the selection of drug candidates. Several studies have shown that advanced PD is associated with GABAergic SPNs characterized by truncated dendrites and a lower number of spines [67,68]. It was also shown in models of PD that depletion of dopamine results in a loss of dendritic spines and glutamatergic synapses on striatopallidal SPNs [69]. This effect is mediated by activation of the Cav1.3 L-type calcium channel at glutamatergic synapses in the spines of SPNs, and affects D2 SPNs, but not D1 cells. The discovery that Cav1.3 calcium channels may underlie these changes is exciting and represents a novel therapeutic target for PD treatment. It would be interesting to investigate the pharmacological inhibition of Cav1.3 channels in humans, possibly with the Cav1.3 blocker nimodipine, to learn if this will improve the motor signs of PD. Acetylcholine The sources for acetylcholine (ACh) in the basal ganglia include cholinergic neurons in the PPN and cholinergic interneurons in the striatum. ACh mediates its effects via nicotinic (nAChR) and muscarinic receptors (MR) (Figure 5). The extensive functional interaction between the cholinergic and DA systems has been exhaustively reviewed [70]. Centrally active MR antagonists were the first accepted pharmacological treatment for PD, and continue to play a role, particularly in the treatment of certain patients with persistent tremor [71]. The basis for the use of these compounds is that loss of DA innervation of the striatum is associated with increased striatal ACh levels, which contributes to the development of motor signs. Limiting their utility, anticholinergics are often associated with neuropsychiatric and cognitive disturbances [71] which, at least in part, can be attributed to their non-specificity for an MR subtype or brain region. Interestingly, experimental data suggest that alterations of MR4 autoreceptor function 550

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in cholinergic interneurons are responsible for the elevated ACh release in the striatum [72]. Evaluation of RGS4, a protein that causes impaired MR4 function in mice and that is conserved in humans, may be a promising, more specific therapeutic approach for the regulation of striatal ACh levels. Recent data provide striking evidence of a key role of cholinergic neurons in the PPN in the etiology of gait disturbances in PD [62]. Cholinergic PPN neurons undergo degeneration in patients with PD [73]. In two doubleblind, long-term studies of PD patients, electrical stimulation of the PPN region led to reduced falls and improved freezing of gait in some patients [74,75]. Importantly, another study revealed that PD patients with gait and balance abnormalities had a lower number of cholinergic neurons in their PPN than PD patients without these signs or unaffected controls [62]. The same study demonstrated that a cholinergic PPN lesion in monkeys induces changes in gait and posture. The development of a specific pharmacological treatment focusing on stimulation of postsynaptic cholinergic receptors would be a promising strategy for therapy of gait disturbances in PD. Identification of the relevant PPN projection sites and the receptors expressed in these regions would greatly facilitate the accomplishment of this goal. Unfortunately, our current knowledge regarding the expression pattern of nAChRs in the human brain is still incomplete (Figure 5). nAChRs consist of several subunits and their combinations vary between brain regions. Although this increases the complexity of the cholinergic system, it may eventually provide a basis for the development of anatomically selective drugs that can target distinct receptor subgroups. To improve the motor signs of PD and to alleviate LID, preclinical efforts are focusing on the development of drugs that stimulate a6b2- and a4b2containing nicotinic receptors, which appear to play a key role in the release of dopamine from nigrostriatal terminals [70]. Owing to the relative pleiotropy of nAChRs, the development of nAChR-targeting drugs may also be considered for the treatment of memory impairment, emotional disturbances, sleep perturbations, and other features such as pain and olfactory dysfunction. Other neurotransmitter systems Abnormal signaling in PD is not restricted to the aforementioned neurotransmitters. Other molecules play a role in signaling imbalances, including lipids, neuropeptides, and additional neurotransmitters such as adenosine. In particular, adenosine 2A (A2A) receptors are currently attracting much attention as a novel promising target for drug therapy. These receptors are selectively localized to indirect SPNs, where they are able to form heterodimers with D2 [80]. Stimulation of A2A opposes the response of indirect SPNs to dopamine, which outlines the rationale for clinical trials with A2A antagonists in patients with PD. The extensive preclinical and clinical investigations of different A2A antagonists for various potential applications in the therapy of PD have been comprehensively reviewed [81]. Importantly, first short-term, double-blind studies demonstrated that the A2A antagonist istradefylline can reduce the off time in L-DOPA-treated PD patients with

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α3-α7 β2-β4

Cortex

Striatum M1,2,3,4,5 α5,α7 β2-β4

Giant aspiny ACh interneurons: M1,2,3,4,5

Thal. β2-β4

GP

Basal forebrain

SN M5, α6

STN

Brainstem

Muscarinic receptors: (G protein-coupled) M1-Type: 1, 3, 5 M2-Type: 2, 4 Neuronal niconic receptors: (Ligand-gated ion channels) Group II: α7 Group III-1: α2, α3, α4, α6 Group III-2: β2, β4 Group III-3: β3, α5

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Figure 5. Cholinergic innervation and distribution of acetylcholine (ACh) receptors in the brain. Cholinergic neurons are located in the pedunculopontine nucleus (PPN) and the dorsolateral tegmental nuclei in the brainstem, as well as in the nucleus basalis of Meynert and the medial septal nucleus in the basal forebrain. These neurons project axons to almost every other brain area. Moreover, the striatum is heavily innervated by cholinergic interneurons. At the molecular level, the effects of ACh are mediated via nicotinic (nAChRs) and muscarinic receptors (MRs). MRs are expressed at much higher density in the brain than nAChRs. Nine different nAChR subunits (a2–a7 and b2–b4) have been detected in the mammalian brain, and various combinations of five subunits are able to constitute a functional receptor [70]. There is considerable evidence that a4b2 receptors, heteromeric a3 receptors, and homomeric a7 receptors play a predominant role in the brain [76]. The distribution pattern of nAChR subunit mRNAs in the human brain has been investigated to some extent by in situ hybridization and quantitative PCR in postmortem tissue, but is still incomplete to date. The subunits a3–a7 and b2–b4 are expressed in the cortex. a3, a5, a7, and b2–b4 mRNAs were detected in several thalamic regions. In the dorsal striatum, analyses revealed the presence of a5, a7, and b2–b4 mRNAs. a6 mRNA was detected in human substantia nigra (SN) [76,77]. At the protein level, investigations focusing on the expression pattern of human nAChR receptors are significantly hampered by the lack of highly selective tracers and antibodies. Although radioligand binding studies in postmortem tissue provide some information on the presence of a subset of nAChRs in a particular brain region, selective quantification of one specific receptor subtype has not been accomplished to date. More detailed knowledge is available in particular for the nigrostriatal pathway in rodents [70]. MRs constitute a family of five metabotropic receptors that are expressed throughout the mammalian brain. Various MR subtypes can be coexpressed in the same neuronal cell population. Similar to investigations of nAChRs, imaging studies focusing on the distribution of MR subtypes in human brain are hampered by the limited selectivity of the tracers currently available. Despite the sparse knowledge about the expression pattern of MR subtypes in the human brain, data collected in rodents provide a basis for our understanding of cholinergic signaling pathways in the mammalian brain. All five MRs are expressed in the striatum. ACh, via different MRs, substantially shapes the signaling in all striatal cell types [78]. To date, MR5 is the only MR that has been detected in midbrain DA neurons [79]. Abbreviations: GP, globus pallidus; STN, subthalamic nucleus; Thal, thalamus.

motor complications [82–86]. The clinical efficacy of the A2A receptor antagonists tozadenant, istradefylline, and preladenant is being investigated in Phase III trials that have been completed or are in progress (Table 1). The relevance of A2A receptors for the development of LID is not completely understood and further investigations are required for clarification. PET imaging with the A2A antagonist [11C]SCH442416 revealed higher A2A binding in the caudate and putamen in dyskinetic versus non-dyskinetic PD patients or controls [87]. However, another PET study using the istradefylline analog [11C]TMSX only confirmed higher A2A binding in the putamen in PD patients with LID compared to healthy controls; the difference between patients with LID and those without LID was not significant [88].

For some potential drug targets, knowledge about their exact role in PD is still sparse. This includes the endocannabinoid system, which undergoes severe perturbations following dopamine depletion [89]. Cannabinoid receptors, particularly CB1, are very abundant in the striatum, where they modulate synaptic plasticity and control glutamate release in response to dopamine via the D2 receptor in mice [90,91]. Opioid and opioid-like receptors constitute another set of putative novel drug targets. The nociceptin/orphanin FQ receptor antagonist Trap-101 improved the motor signs in a rat model of PD [92]. However, studies in primates suggest that these antagonists have the potential to worsen LID, thereby limiting their clinical usefulness [93]. Neuropeptide systems in the basal ganglia (e.g., substance P, enkephalin, 551

Review dynorphin, neuropeptide Y, somatostatin, and cholecystokinin) may also have relevance for the treatment of PD. Future directions For several neurotransmitter receptor families, the expression map in the human brain is still incomplete. Importantly, our knowledge regarding the effect of various parameters on the expression levels of receptors and transporters is very sparse. PD-related factors that are likely to have an impact include the age of onset, disease duration, drug treatment, and the development of LID or depression. Greater cellular, subcellular, and molecular resolution of the expression profiles, linked to diseasespecific changes, would further facilitate the identification of therapeutic approaches. Although preclinical investigations are vital during the initial stages of the drug development process, it must be considered that rodent and non-human primate models can only partly recapitulate the pathological changes that occur in patients with PD. The expression patterns of neurotransmitter receptors and transporters in normal and disease-like states, the conformation, the subunit composition and the interacting partners of receptors, as well as the binding affinity between a specific drug target and a test compound are only some of the parameters that may vary significantly between species. These factors present a challenge for the translation of therapeutic strategies from disease models to patients and highlight the importance of validating preclinical data in human tissue or subjects whenever feasible. The development of novel, highly selective markers for in vivo imaging studies would greatly facilitate investigations focusing on receptor expression changes in PD patients. Thus, future studies could: (i) confirm the involvement of D1 in dyskinesias, (ii) better characterize the expression pattern of 5-HT receptors (e.g., 5-HT2A) in limbic brain regions, (iii) study the correlation between a2 receptor antagonism and LID, (iv) refine mGluR and nAChR expression maps, (v) identify the complete set of receptors expressed by cholinergic interneurons in the striatum, (vi) determine the adrenoceptors, glutamatoceptors, and cholinoceptors that are involved in the etiology of gait disorders, and (vii) further characterize the regulation of MR4 by RGS4. Indeed, targeting of upstream regulators of receptors might represent an option for pharmacological intervention when receptor selectivity cannot be reached. In addition, the crosstalk between different receptor types that are localized within the same neuron might provide alternative targets for modulating receptor activity, which is exemplified by the interaction between the D2 and A2A receptors in indirect SPNs and the development of A2A antagonists. Further exploration of the interaction between the A2A receptor and the fibroblast growth factor receptor might be another innovative selective treatment approach [94]. Concluding remarks Dopamine replacement therapy with L-DOPA represents the most effective current treatment for PD. However, this treatment is not ideal. Not all features of PD respond to L-DOPA, and those that do respond may only do so transiently. Numerous challenges remain to further 552

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advance the clinical management of this disease. Non-DA neurotransmitter systems in the brain are significantly perturbed in PD, and these abnormalities, as well as the physical and functional interaction between the different neurotransmitter systems, substantially contribute to the development of the manifestations of PD. Consequently, the receptors and transporters of DA and non-DA neurotransmitter systems are promising therapeutic targets for the treatment of PD. This is evident from the growing number of clinical trials with drugs targeting these systems. Completing and refining expression maps for the various neurotransmitter receptors in the human brain, investigating changes in receptor and transporter densities in PD in both a brain-region-specific and cell-typespecific manner, and optimizing therapeutic approaches through clinical trials specific for PD will facilitate the development of further innovative treatment options. Acknowledgments We thank Serge Przedborski for valuable suggestions and discussions on this topic, Elisabeth Griggs for assistance with graphic design, and Joseph Terlizzi for commenting on the manuscript. L.B. is supported by US Army Medical Research contract W81XWH-10-1-0640 and W81XWH12-1-0039. P.G. is supported by US Army Medical Research contract W81XWH-09-1-0402, the JPB Foundation, and the Brain Research Foundation. M.F. is supported by US Army Medical Research contract W81XWH-10-1-0691.

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