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Brain α7 nicotinic acetylcholine receptors in MPTP-lesioned monkeys and parkinsonian patients
Biochemical Pharmacology 109 (2016) 62–69
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Brain a7 nicotinic acetylcholine receptors in MPTP-lesioned monkeys and parkinsonian patients Marc Morissette b,1, Nicolas Morin a,b,1, Laurent Grégoire b, Alex Rajput c, Ali H. Rajput c, Thérèse Di Paolo a,b,⇑ a b c
Faculty of Pharmacy, Université Laval, Quebec City G1K 7P4, Canada Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK S7N 0W8, Canada
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Article history: Received 5 February 2016 Accepted 29 March 2016 Available online 30 March 2016 Keywords: a7 nicotinic acetylcholine receptor Parkinson’s disease L-DOPA-induced dyskinesia Human MPTP-lesioned monkey
a b s t r a c t L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson’s disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain a7 nACh receptors might be a potential therapeutic target for PD. This study used [125I]aBungarotoxin autoradiography to investigate a7 nACh receptors in LID in post-mortem brains from PD patients (n = 14) and control subjects (n = 11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n = 5), L-DOPA (n = 4) or L-DOPA + 2-methyl-6-(phenyle thynyl)pyridine (MPEP) (n = 5), and control monkeys (n = 4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [125I]a-Bungarotoxin specific binding to striatal and pallidal a7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA + MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [125I]a-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [125I]a-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [125I]a-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [125I]a-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal a7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD. Ó 2016 Elsevier Inc. All rights reserved.
1. Introduction
Abbreviations: AIMs, abnormal involuntary movements; BSA, bovine serum albumin; DA, dopamine; DL, dorsolateral; DM, dorsomedial; GP, globus pallidus; GPe, external globus pallidus; GPi, internal globus pallidus; Hepes, 2-[4-(2-hydrox yethyl)-1-piperazinyl] ethanesulfonic acid; KRH, Krebs-Ringer Hepes; L-DOPA, L3,4-dihydroxyphenylalanine; LID, L-DOPA-induced dyskinesias; mGlu, metabotropic glutamate; MPEP, 2-methyl-6-(phenylethynyl)pyridine; MPTP, 1-methyl-4-ph enyl-1,2,3,6-tetrahydropyridine; nACh, nicotinic acetylcholine; NAM, negative allosteric modulator; PD, Parkinson’s disease; VL, ventrolateral; VM, ventromedial. ⇑ Corresponding author at: Neuroscience Research Unit, Centre de recherche du CHU de Québec, 2705 Laurier Boulevard, Quebec, Qc G1V 4G2, Canada. E-mail addresses: [email protected] (M. Morissette), [email protected] (N. Morin), [email protected] (L. Grégoire), [email protected] (A. Rajput), [email protected] (A.H. Rajput), [email protected] (T. Di Paolo). 1 Marc Morissette and Nicolas Morin are co-first authors and have contributed equally to this manuscript. http://dx.doi.org/10.1016/j.bcp.2016.03.023 0006-2952/Ó 2016 Elsevier Inc. All rights reserved.
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is likely to increase due to the aging population [1]. The cardinal motor manifestations of PD, tremor, bradykinesia, and rigidity, are secondary to a loss of striatal dopamine (DA) due DA neuron death in the substantia nigra [2]. Following chronic treatment with L-DOPA, motor complications including L-DOPA-induced dyskinesias (LID) and wearing-off appear in most parkinsonian patients [3]. Decreasing the dose of L-DOPA can decrease LID but usually worsens PD symptoms [4] hence alternative approaches are needed to effectively treat advanced PD. Other neurotransmitters and neuromodulators, such as glutamate, serotonin and acetylcholine are also affected in PD [5]. Striatal cholinergic interneurons are indispensable in controlling striatal neuronal activity and extrapyramidal motor movement
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[6]. Evidence indicates that the imbalance between cholinergic and dopaminergic systems plays a fundamental role in PD movement abnormalities [7]. Moreover, the ability of nicotine and nicotinic acetylcholine (nACh) receptor agonists to alleviate LID in parkinsonian animal models supports a role for the cholinergic system in LID [8,9]. nACh receptors are located mainly presynaptically modulating synaptic activity by regulation of neurotransmitter release [10]. a7 nACh receptors are highly expressed at glutamatergic terminals in the striatum [11] and their activation stimulates release of glutamate from corticostriatal terminals [12]. Our hypothesis is that LID are associated with changes in a7 nACh receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri dine (MPTP)-lesioned monkey model of PD and human parkinsonian post-mortem brains. To our knowledge, no study reported the effect of a metabotropic glutamate (mGlu) 5 receptor negative allosteric modulator (NAM) on brain a7 nACh receptors in parkinsonian monkeys. Our objectives were thus 1- to investigate the long-term effect of the prototypal mGlu5 receptor NAM, 2-methy l-6-(phenylethynyl)pyridine (MPEP) with L-DOPA that reduced development of LID on basal ganglia a7 nACh receptors in MPTP monkeys and 2- to verify if changes in a7 nACh receptors are associated with development of motor complications in L-DOPAtreated parkinsonian patients. 2. Materials and methods
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2.4. Human subjects Samples from PD patients of this study were previously investigated [15]. The clinical profiles of patients, their LID and wearingoff were well documented [16]. Wearing-off was defined as a predictable decline in motor benefit at the end of the dose in a patient with a previously stable response [16]. Patients were divided into groups based on the development of motor complications. These groups were not statistically different with respect to sex, age of death, brain pH, age of PD onset, duration of PD, duration of LDOPA use, average daily dose of L-DOPA, cumulative L-DOPA dose, duration of follow-up, and age at L-DOPA initiation. Eleven control patients (2 women and 9 men) were also studied. Delay to autopsy of the control subjects was <24 h and was not different from the delays for PD patients. The age at death of control subjects was 68 ± 3 and PD patients 78 ± 2 years (p < 0.01). Information on the smoking status of the controls was not available except for one who was a non-smoker and another that smoked 15 years but quit 15 years before death. All PD patients without dyskinesias were non-smokers except one that smoked until the age of 62 and died at age 69. All dyskinetic PD patients were non-smokers except for one for whom this information was not available and another noted not to smoke terminally. Twelve of the 14 PD patients had received anticholinergic drugs, one that displayed no motor complications and the other with dyskinesias only [17].
2.1. Animals and treatments This experiment used 18 drug naive female ovariectomized monkeys (Macaca fascicularis) (aged 4.7–7.7 years; weight: 2.7– 4.2 kg; Covance Research Products, China) in agreement with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The Laval University committee for the protection of animals approved this study. This study complies with the ARRIVE guidelines and all efforts were made to minimize animal suffering, to reduce the number of animals used, and to utilize alternatives to in vivo techniques, if they were available. Motor behavior of these monkeys was previously reported [13]. One group of monkeys (n = 4) remained untreated and served as controls and the others were rendered parkinsonian with MPTP (Sigma–Aldrich Canada Ltd., Oakville, ON, Canada). Five MPTP monkeys received saline (saline MPTP group), while four others received one month daily oral treatment with L-DOPA/benserazide alone (100/25 mg; ProlopaÒ) (Hoffmann-La Roche limited, Mississauga, ON, Canada) and the five remaining animals received L-DOPA/benserazide (same dosage) and MPEP (10 mg/kg, Novartis Pharma AG, Basel, Switzerland). L-DOPA improved parkinsonian scores, this response was unaffected by adding MPEP [13]. The mean dyskinesia score increased over a month in both L-DOPA-treated groups, but significantly less in L-DOPA + MPEP-treated monkeys [13]. 2.2. Animal tissue preparation Animals were killed 24 h after their last dose of L-DOPA and brains stored at 80 °C. Brains were cut into 12-lm coronal sections on a cryostat ( 18 °C). The posterior striatum from levels A15–A18 [14] was investigated. Slices were thaw-mounted onto SuperFrost Plus slides (Brain Research Laboratories, Newton, MA) and stored at 80 °C until assayed. Brain tissues were also collected to measure the extent of the lesion. 2.3. Animal DA denervation assays DA contents were measured by HPLC [13]. The MPTP lesion led to a similar extensive 98–99% reduction of striatal DA contents of all MPTP monkeys of this experiment [13].
2.5. Autopsy and handling of brain material Autopsies of all human subjects confirmed the PD diagnosis and showed marked neuronal loss in the substantia nigra pars compacta, presence of Lewy body, and absence of other pathological changes that may account for parkinsonian symptoms [16]. 2.6. Measures of extent of dopamine denervation in human brain There was a marked decrease in DA ( 98.8%) contents in the putamen of all PD patients compared with controls and no difference among the subgroups of PD patients [15]. 2.7. Autoradiography of a7 nACh receptors [125I]a-Bungarotoxin (143.8 Ci/mmol: Perkin Elmer, Boston, MA, USA) autoradiography was used to label a7 nACh receptors as reported [18]. Brain sections were pre-incubated for 30 min in a Krebs-Ringer Hepes buffer (KRH buffer) containing 20 mM Hepes (2-[4-(2-hydroxyethyl)-1-piperazinyl] ethanesulfonic acid), 118 mM NaCl, 4.8 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, and 10 mM NaOH (all products are from Sigma–Aldrich Canada Ltd., Oakville, ON, Canada), pH 7.4. The slides were then incubated for 120 min at room temperature with 50 nM [125I]a-Bungarotoxin in KRH buffer containing 0.05% bovine serum albumin (BSA) (EDM Millipore, Etobicoke, ON, Canada). To determine nonspecific binding, 50 lM ( )Nicotine (Sigma, Oakville, ON, Canada) was added to four human and four monkey brain sections. Nonspecific binding was also estimated with a measure of a constant area outside the caudate–putamen for each brain slice. A region of the same dimension was measured on each section at the level of internal capsule for human and monkey sections; for monkeys, a region near the caudate in the white matter was measured when the space between the caudate and putamen was too small. After incubation, slides were washed three times for 20 min in 20 mM KRH buffer, pH 7.4 at 4 °C, then rinsed in distilled water at 4 °C and allowed to air-dry overnight. Sections were then exposed to [125I]-sensitive films (Kodak BIOMAX MR, USA) for 2 weeks at room
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temperature. Films were developed and autoradiograms were analyzed by densitometry. 2.8. Image, data and statistical analysis The intensity of autoradiograms was quantified with a Power Macintosh G4 connected to a video camera (XC-77; Sony) and a constant-illumination light table using computerized densitometry (NIH image v.1.63). A standard grayscale strip (Stouffer Graphic Arts Equipment Co. Inc., IN, USA) was used to generate a calibration curve for optical densities. Optical gray densities were transformed into nCi/mg of tissue equivalent using a standard curve generated with standard [125I]-strips (GE Healthcare Life Sciences, Mississauga, ON, Canada). For each brain regions investigated, 4 brain slices for each human and animal were used for autoradiographic analyses. Statistical comparison of monkey results was performed by a two-way analysis of variance with putamen and globus pallidus subregions and treatments as factors, followed by post-hoc pairwise comparisons with Fisher’s least significant difference test. The caudate nucleus of monkeys was small at the brain region investigated, hence it was not subdivided into subregions and the whole area was analyzed by a one-way analysis of variance with treatment as factor, followed by post-hoc pairwise comparisons with Fisher’s least significant difference test. Human results were analyzed by a one-way analysis of variance with treatment as factor, followed by post-hoc pairwise comparisons with Fisher’s least significant difference test. Non-specific binding, estimated from each brain slice or from other brain slices in the presence of ( ) Nicotine, was subtracted from total binding and was used to generate two estimates of [125I]a-Bungarotoxin specific binding. The statistical analysis of both these specific binding values gave similar statistical changes and only one is presented. First, control subjects (n = 10) were compared to all PD patients (n = 14). Second, controls were compared to PD patients without motor complications (n = 4), with dyskinesias only (n = 4), with wearing-off only (n = 3) and with dyskinesia + wearing-off (n = 3). A simple regression model was used to determine coefficients of correlation and the significance of the degree of linear
relationship between the mean dyskinesia scores of the MPTPlesioned monkeys (n = 14, from the last week of behavioral observations [13]) and specific binding values. A value of p < 0.05 was considered significant.
3. Results 3.1. [125I]a-Bungarotoxin specific binding in monkey brains Fig. 1 shows examples of [125I]a-Bungarotoxin binding in a control and MPTP monkeys compared to non-specific binding. [125I]a-Bungarotoxin specific binding increased in the caudate nucleus (effect of treatment: F3,14 = 17.03, p < 0.0001; Fig. 2A), putamen (effect of treatment: F3,14 = 20.64, p < 0.0001; subregion: F3,42 = 20.11, p < 0.0001; interaction: F9,42 = 4.34, p < 0.001; Fig. 2B) and GP (effect of treatment: F3,14 = 9.39, p < 0.01; subregion: F1,14 = 65.83, p < 0.0001; interaction: F3,14 = 7.39, p < 0.01; Fig. 2C) of L-DOPA-treated MPTP monkeys compared to controls as well as saline and L-DOPA + MPEP treated MPTP groups (+39%, +38% and +40% for caudate nucleus, +34%, +32% and +43% for putamen and +42%, +23% and +27% for GP vs. each group respectively). [125I]a-Bungarotoxin specific binding did not change in the L-DOPA + MPEP-treated MPTP group compared to controls and saline-treated MPTP monkeys in the caudate nucleus, putamen and GP. The mean dyskinesia scores of the MPTP monkeys (n = 14) correlated positively with their striatal and pallidal [125I]a-Bungarotoxin specific binding (Fig. 3). 3.2. [125I]a-Bungarotoxin specific binding in human brains Fig. 4 shows examples of [125I]a-Bungarotoxin binding in controls and PD patients as well as non-specific binding. As compared to control subjects, [125I]a-Bungarotoxin specific binding of PD patients increased significantly in the caudate nucleus (+49%; Fig. 5A; F1,24 = 11.87, p < 0.01) whereas no change was observed in putamen (Fig. 5A) and GP (data not shown).
Fig. 1. Examples of [125I]a-Bungarotoxin binding to brain a7 nicotinic acetylcholine receptors showing an elevation in dyskinetic L-DOPA treated monkeys compared to a control, a MPTP-lesioned monkeys treated with saline and L-DOPA + MPEP treatment. Non-specific binding in the presence of ( )Nicotine is also shown. Schematic of the brain and regions analyzed is also presented. DM, dorsomedial; VM, ventromedial; VL, ventrolateral; DL, dorsolateral; external (GPe) and internal (GPi) globus pallidus.
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Fig. 2. Autoradiography of monkey brain a7 nicotinic acetylcholine receptors showing an increase in this receptor in LID. [125I]a-Bungarotoxin specific binding in the caudate nucleus (A) and putamen (B) of control monkeys (n = 4), and MPTP-lesioned monkeys treated with saline (n = 5), L-DOPA (n = 4) and L-DOPA + MPEP (n = 5). (C) [125I]a-Bungarotoxin specific binding in the external (GPe) and internal (GPi) globus pallidus of these monkeys. Data are expressed as mean ± SEM. One hundred percent control values (fmol/mg of tissue) were for the caudate nucleus, 0.467; for the putamen, DM = 0.466, VM = 0.483, DL = 0.491, VL = 0.513; and for the GP, GPe = 0.479, GPi = 0.532. ***p < 0.001 and ****p < 0.0001 vs. control monkeys; ##p < 0.01 and ###p < 0.001 vs. MPTP + saline-treated monkeys; ++p < 0.01, +++p < 0.001 and ++++p < 0.0001 vs. MPTP + L-DOPA-treated monkeys. DM, dorsomedial; VM, ventromedial; VL, ventrolateral; DL, dorsolateral.
As compared to control subjects, [125I]a-Bungarotoxin specific binding increased in the caudate nucleus of PD patients without and with motor complications, including PD patients with dyskinesias only and with dyskinesia + wearing-off (+45%, +68% and +60% vs. control subjects respectively; Fig. 5B; F4,20 = 4.49, p < 0.05) whereas no increase was observed in PD patients with wearingoff only. [125I]a-Bungarotoxin specific binding of PD patients with wearing-off only were lower than PD patients with dyskinesia in the caudate nucleus ( 38%). In the putamen, as compared to control subjects and PD patients without motor complications, [125I]a-Bungarotoxin specific binding only increased in PD patients with motor complications with dyskinesias only (+23% and +21% respectively; Fig. 5B; F4,20 = 6.73, p < 0.01) whereas the specific binding decreased in PD patients with wearing-off only ( 25% and 26% respectively; Fig. 5B; F4,20 = 6.73, p < 0.01). Specific binding levels of PD patients with dyskinesia and wearing-off were unchanged compared to control subjects and PD patients without motor complications. [125I]a-Bungarotoxin specific binding levels were higher in PD patients with dyskinesias only compared to PD patients with wearing-off only and PD patients with dyskinesia and wearingoff (+64% and +48% respectively; Fig. 5B; F4,20 = 6.73, p < 0.01).
No change was observed between the different groups of humans in GPe and GPi (Fig. 5C). 4. Discussion The present results are the first to show in the putamen elevated a7 nACh receptor specific binding of dyskinetic PD patients and MPTP monkeys with LID. The dyskinesia scores of MPTP monkeys correlated positively with their a7 nACh receptor specific binding with the highest correlation in the putamen implicated in motor control. A chronic mGlu5 receptor NAM treatment reducing development of LID inhibited striatal and pallidal elevation of a7 nACh receptor specific binding. The nACh receptor modulation, including a7 nACh receptors, by their agonists is not straightforward with the assumption that an agonist will replace or augment the stimulation provided by the natural activator [19]. For most nACh receptor subtypes a primary effect of the prolonged presence of an agonist is to produce desensitization, decreasing the effect of the normal fluctuations in ACh signaling [20]. Hence, the increase in a7 nACh receptors in LID would benefit from an agonist treatment that would desensitize (decrease functional activity) this receptor. Behaviorally, the a7
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Fig. 3. Positive correlations between mean dyskinesia scores of these monkeys and their [125I]a-Bungarotoxin specific binding (shown in Fig. 2) in the caudate nucleus (A), putamen (B), GPe (C) and GPi (D); each point represents an individual monkey.
Fig. 4. Examples of [125I]a-Bungarotoxin binding autoradiography to a7 nicotinic acetylcholine receptors in brain sections of a post-mortem control subject and L-DOPAtreated parkinsonian patients showing an elevation with LID. Non-specific binding in the presence of ( )Nicotine is also shown. The schematic of the human basal ganglia sections showing, the caudate nucleus (caudate), putamen, GPe and GPi was adapted from the Atlas of the human brain [45].
nACh receptor selective partial agonist, AQW051, alleviates LID in MPTP monkeys with an extension of the duration of L-DOPA antiparkinsonian activity [21]. The a7 nACh receptor agonist ABT-107 also decreases LID in parkinsonian monkeys [22]. Moreover, Ro 61–8048 that antagonizes glutamate receptors and inhibits a7 nACh receptors reduces development of LID in MPTP monkeys [23] and its expression in already dyskinetic MPTP monkeys [24]. These findings support the contribution of a7 nACh receptors in LID and their targeting for a possible novel therapeutic
treatment. Moreover, a7 nACh receptor agonists display neuroprotective activity in animal models of PD [25–27]. Distribution of a7 nACh receptor in monkeys [28] and healthy subjects [29] shows binding in the putamen, the caudate nucleus and GP as reported in the present study. A MPTP regimen leading to symptomatic motor impairment in monkeys was reported to increase [125I]a-Bungarotoxin specific binding only in the dorsolateral putamen [18]. By contrast, these authors showed an increase in all subregions of the putamen in asymptomatic MPTP
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Fig. 5. Autoradiography of human brain a7 nicotinic acetylcholine receptors showing an increase in this receptor in LID. (A) [125I]a-Bungarotoxin specific binding to a7 nicotinic acetylcholine receptors in the caudate nucleus and putamen of post-mortem human brain tissue from controls (n = 10) compared to all parkinsonian subjects (n = 14). (B) [125I]a-Bungarotoxin specific binding in the caudate nucleus and putamen of post-mortem human brain tissue from controls (n = 10) compared to parkinsonian subjects with motor complications or not following L-DOPA therapy (n=4 without motor complications group: 3 non-smokers and 1 smoked until age 62 and died at 69; n = 4 for dyskinesias only group: 2 non-smokers, 1 did not smoke terminally and 1 not available; n = 3 for wearing-off only group: all non-smokers and n = 3 for wearing-off + dyskinesias group: all non-smokers). (C) [125I]a-Bungarotoxin specific binding in the GPe and GPi of these subjects. Data are expressed as mean ± SEM. One hundred percent control values (fmol/mg of tissue) were for the caudate nucleus = 0.102, putamen = 0.151, GPe = 0.124 and GPi = 0.107. *p < 0.05 and **p < 0.01 vs. controls; &p < 0.05 vs. PD patients with dyskinesia only; #p < 0.05 vs. PD patients without motor complications. PD, Parkinson’s disease.
monkeys suggesting that this increase may be part of a compensatory process to help maintain motor functions in the earliest stages of PD. Accordingly, our vehicle-treated MPTP monkeys modeling late stages of the disease did not show increased [125I] a-Bungarotoxin specific binding in the putamen. In relation to LID, the effect in MPTP monkeys of L-DOPA and MPEP treatments on a7 nACh receptors is not yet available for comparison with the present results. It is nevertheless important to investigate the effects of mGlu5 receptor NAMs on nACh receptors since they are the object of intense research for various CNS diseases [30–32]. Nor are there reports on brain a7 nACh receptors of PD patients
in relation to motor complications. However, epidemiological studies show a decrease in PD in smokers [33] with an overall 50% decline in the risk of PD in tobacco users [34,35]. There are no reports on [125I]a-Bungarotoxin specific binding in the caudate nucleus and putamen in relation to aging of the human brain. However, there are reports of generalized loss of different nicotinic receptor subtypes in aging in various brain areas but only after the 70th decade in the striatum [36,37]. Moreover, no change of a7 nicotinic acetylcholine receptor mRNA was observed in the putamen between the age of 22–80 years [38]. The differences of a7 nACh specific binding among the human subjects investigated is
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unlikely due to the younger age of the controls compared to the PD patients since their binding was similar in the putamen (Fig 5A) and GP (Fig 5C). In the caudate nucleus the difference between the controls and the PD patients is more likely related to their motor complication rather than the age difference as Fig 5B shows. The a7 nACh receptor changes observed in the human brain investigated were unlikely related to their tobacco use since differences were observed between PD patients in relation to their motor complications and most of these patients were non-smokers. Moreover, these receptor changes were unlikely related to anticholinergic drug use since differences were observed between PD patients in relation to their motor complications and only one PD patient without motor complications and one with dyskinesias only did not receive anticholinergic drugs [17]. In animal models of PD, no data are available on the effect of anticholinesterase inhibitors on striatal a7 nACh receptor binding; one report showed in intact rats, no effect of chronic donepezil treatment on striatal a7 nACh receptors [39] and a study showed no effect of a chronic treatment in aged rats of the anticholinesterase inhibitors galantamine or donepezil on ambulatory activity [40]. Furthermore, the receptor changes in PD patients in relation to LID were similar to those observed in MPTP monkeys with LID and the latter were of similar age, never exposed to tobacco and they were drug naive at the start of the experiment. The MPTP monkeys of this experiment never received non-dopaminergic drugs except for those that were administered MPEP. Nevertheless as this manuscript showed, as well as our previous studies of the brain of these animals, the LDOPA and MPEP treatment affected various neurotransmitters and neuromodulators [13,41–44]. The a7 nACh receptor changes observed in PD and MPTP monkeys treated with chronic L-DOPA are more likely associated with the development of dyskinesias rather than the chronic L-DOPA treatment per se since the cumulative dose of L-DOPA was similar in the PD patients with and without motor complications [17] and the MPTP monkeys received similar doses in the chronic L-DOPA than the L-DOPA + MPEP groups. In the putamen, we observed no change in a7 nACh receptors of PD patients with no motor complications and in saline-treated MPTP monkeys. In addition, in the putamen of PD patients with dyskinesias only and MPTP monkeys treated with L-DOPA that developed LID, a7 nACh receptor specific binding was elevated. Hence, both in PD patients and parkinsonian monkeys an increase in a7 nACh receptors was observed in the putamen supporting relevance of this animal model and the implication of these receptors in relation to LID. PD patients that developed wearing-off only did not have an increase in striatal and pallidal a7 nACh receptor specific binding suggesting that this motor complication does not involve this nicotinic receptor. PD patients with dyskinesias and wearing-off had reduced a7 nACh receptor specific binding in putamen but elevated values in the caudate nucleus. Moreover, PD patients with no motor complications had elevated a7 nACh receptor specific binding compared to controls in the caudate nucleus. More research is required to decipher these latter findings. No change of pallidal a7 nACh receptor specific binding was observed in PD patients associated with the disease or motor complications. Similarly, in monkeys the MPTP lesion did not change pallidal a7 nACh receptor specific binding whereas elevated values were observed in dyskinetic MPTP monkeys. More research is required to further investigate pallidal a7 nACh receptors in relation to dyskinesias. In conclusion, the present results show a consistent elevation of basal ganglia a7 nACh receptor specific binding in LID in PD patients as well as in a non-human primate model of PD supporting the relevance of targeting this receptor to treat dyskinesias.
Conflict of interest Authors have no conflict of interest concerning this study and have nothing to declare. Acknowledgements This work was supported by a grant from the Canadian Institutes of Health Research to TDP (MOP-114916). N.M. held a professional health care studentship from the Fonds de la recherche en santé du Québec (FRSQ). References [1] A. Siderowf, M. Stern, Update on Parkinson disease, Ann. Intern. Med. 138 (8) (2003) 651–658. [2] C.W. Olanow, M.B. Stern, K. Sethi, The scientific and clinical basis for the treatment of Parkinson disease (2009), Neurology 72 (21 Suppl. 4) (2009) S1– S136, http://dx.doi.org/10.1212/WNL.0b013e3181a1d44c. [3] G. Fabbrini, J.M. Brotchie, F. Grandas, M. Nomoto, C.G. Goetz, Levodopainduced dyskinesias, Mov. Disord. 22 (10) (2007) 1379–1389, http://dx.doi. org/10.1002/mds.21475. quiz 1523. [4] N.B. Mercuri, G. Bernardi, The ’magic’ of L-dopa: why is it the gold standard Parkinson’s disease therapy? Trends Pharmacol. Sci. 26 (7) (2005) 341–344, http://dx.doi.org/10.1016/j.tips.2005.05.002. [5] P. Huot, T.H. Johnston, J.B. Koprich, S.H. Fox, J.M. Brotchie, The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease, Pharmacol. Rev. 65 (1) (2013) 171–222, http://dx.doi.org/10.1124/pr.111.005678. [6] F.M. Zhou, C.J. Wilson, J.A. Dani, Cholinergic interneuron characteristics and nicotinic properties in the striatum, J. Neurobiol. 53 (4) (2002) 590–605, http:// dx.doi.org/10.1002/neu.10150. [7] S. Kaneko, T. Hikida, D. Watanabe, H. Ichinose, T. Nagatsu, R.J. Kreitman, I. Pastan, S. Nakanishi, Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function, Science 289 (5479) (2000) 633–637. [8] M. Quik, D. Zhang, M. McGregor, T. Bordia, Alpha7 nicotinic receptors as therapeutic targets for Parkinson’s disease, Biochem. Pharmacol. 97 (4) (2015) 399–407, http://dx.doi.org/10.1016/j.bcp.2015.06.014. [9] M. Quik, T. Bordia, D. Zhang, X.A. Perez, Nicotine and nicotinic receptor drugs: potential for Parkinson’s disease and drug-induced movement disorders, Int. Rev. Neurobiol. 124 (2015) 247–271, http://dx.doi.org/10.1016/bs. irn.2015.07.005. [10] S. Wonnacott, Presynaptic nicotinic ACh receptors, Trends Neurosci. 20 (2) (1997) 92–98. [11] G.G. Nomikos, B. Schilstrom, B.E. Hildebrand, G. Panagis, J. Grenhoff, T.H. Svensson, Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness, Behav. Brain Res. 113 (1–2) (2000) 97–103. [12] M. Marchi, F. Bergaglia, A. Pedrini, M. Raiteri, Study of the bidirectional transport of choline by blocking choline carriers from outside or inside brain nerve terminals, J. Neurosci. Res. 61 (5) (2000) 533–540. [13] N. Morin, L. Gregoire, M. Morissette, S. Desrayaud, B. Gomez-Mancilla, F. Gasparini, T. Di Paolo, MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates, Neuropharmacology 66 (2013) 355–364, http://dx.doi.org/10.1016/j.neuropharm.2012.07.036. [14] J. Szabo, W.M. Cowan, A stereotaxic atlas of the brain of the cynomolgus monkey (Macaca fascicularis), J. Comp. Neurol. 222 (2) (1984) 265–300, http:// dx.doi.org/10.1002/cne.902220208. [15] F. Calon, A.H. Rajput, O. Hornykiewicz, P.J. Bedard, T. Di Paolo, Levodopainduced motor complications are associated with alterations of glutamate receptors in Parkinson’s disease, Neurobiol. Dis. 14 (3) (2003) 404–416. [16] A.H. Rajput, M.E. Fenton, S. Birdi, R. Macaulay, D. George, B. Rozdilsky, L.C. Ang, A. Senthilselvan, O. Hornykiewicz, Clinical-pathological study of levodopa complications, Mov. Disord. 17 (2) (2002) 289–296. [17] F. Calon, M. Morissette, A.H. Rajput, O. Hornykiewicz, P.J. Bedard, T. Di Paolo, Changes of GABA receptors and dopamine turnover in the postmortem brains of parkinsonians with levodopa-induced motor complications, Mov. Disord. 18 (3) (2003) 241–253, http://dx.doi.org/10.1002/mds.10343. [18] J.M. Kulak, J.S. Schneider, Differences in alpha7 nicotinic acetylcholine receptor binding in motor symptomatic and asymptomatic MPTP-treated monkeys, Brain Res. 999 (2) (2004) 193–202, http://dx.doi.org/10.1016/j. brainres.2003.10.062. [19] D.K. Williams, J. Wang, R.L. Papke, Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations, Biochem. Pharmacol. 82 (8) (2011) 915–930, http://dx.doi.org/10.1016/j.bcp.2011.05.001. [20] M.R. Picciotto, N.A. Addy, Y.S. Mineur, D.H. Brunzell, It is not ‘‘either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood, Prog. Neurobiol. 84 (4) (2008) 329–342, http://dx.doi.org/10.1016/j. pneurobio.2007.12.005.
M. Morissette et al. / Biochemical Pharmacology 109 (2016) 62–69 [21] T. Di Paolo, L. Gregoire, D. Feuerbach, W. Elbast, M. Weiss, B. Gomez-Mancilla, AQW051, a novel and selective nicotinic acetylcholine receptor alpha7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of lDopa effects in parkinsonian monkeys, Parkinsonism Relat. Disord. 20 (11) (2014) 1119–1123, http://dx.doi.org/10.1016/j.parkreldis.2014.05.007. [22] D. Zhang, M. McGregor, M.W. Decker, M. Quik, The alpha7 nicotinic receptor agonist ABT-107 decreases L-Dopa-induced dyskinesias in parkinsonian monkeys, J. Pharmacol. Exp. Ther. 351 (1) (2014) 25–32, http://dx.doi.org/ 10.1124/jpet.114.216283. [23] L. Gregoire, A. Rassoulpour, P. Guidetti, P. Samadi, P.J. Bedard, E. Izzo, R. Schwarcz, T. Di Paolo, Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys, Behav. Brain Res. 186 (2) (2008) 161–167, http://dx.doi.org/10.1016/j. bbr.2007.08.007. [24] P. Samadi, L. Gregoire, A. Rassoulpour, P. Guidetti, E. Izzo, R. Schwarcz, P.J. Bedard, Effect of kynurenine 3-hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in Parkinsonian monkeys, Mov. Disord. 20 (7) (2005) 792–802, http://dx.doi.org/10.1002/mds.20596. [25] S. Suzuki, J. Kawamata, T. Matsushita, A. Matsumura, S. Hisahara, K. Takata, Y. Kitamura, W. Kem, S. Shimohama, 3-[(2,4-Dimethoxy)benzylidene]anabaseine dihydrochloride protects against 6-hydroxydopamine-induced parkinsonian neurodegeneration through alpha7 nicotinic acetylcholine receptor stimulation in rats, J. Neurosci. Res. 91 (3) (2013) 462–471, http:// dx.doi.org/10.1002/jnr.23160. [26] V. Stuckenholz, M. Bacher, M. Balzer-Geldsetzer, D. Alvarez-Fischer, W.H. Oertel, R.C. Dodel, C. Noelker, The alpha7 nAChR agonist PNU-282987 reduces inflammation and MPTP-induced nigral dopaminergic cell loss in mice, J. Parkinsons Dis. 3 (2) (2013) 161–172, http://dx.doi.org/10.3233/JPD-120157. [27] T. Bordia, M. McGregor, R.L. Papke, M.W. Decker, J.M. McIntosh, M. Quik, The alpha7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions, Exp. Neurol. 263 (2015) 277–284, http://dx.doi.org/10.1016/j.expneurol.2014.09.015. [28] A.G. Horti, Y. Gao, H. Kuwabara, Y. Wang, S. Abazyan, R.P. Yasuda, T. Tran, Y. Xiao, N. Sahibzada, D.P. Holt, K.J. Kellar, M.V. Pletnikov, M.G. Pomper, D.F. Wong, R.F. Dannals, 18F-ASEM, a radiolabeled antagonist for imaging the alpha7-nicotinic acetylcholine receptor with PET, J. Nucl. Med. 55 (4) (2014) 672–677, http://dx.doi.org/10.2967/jnumed.113.132068. [29] D.F. Wong, H. Kuwabara, M. Pomper, D.P. Holt, J.R. Brasic, N. George, B. Frolov, W. Willis, Y. Gao, H. Valentine, A. Nandi, L. Gapasin, R.F. Dannals, A.G. Horti, Human brain imaging of alpha7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancy, Mol. Imaging Biol. 16 (5) (2014) 730–738, http://dx.doi.org/10.1007/s11307-0140779-3. [30] G. Jaeschke, S. Kolczewski, W. Spooren, E. Vieira, N. Bitter-Stoll, P. Boissin, E. Borroni, B. Buttelmann, S. Ceccarelli, N. Clemann, B. David, C. Funk, W. Guba, A. Harrison, T. Hartung, M. Honer, J. Huwyler, M. Kuratli, U. Niederhauser, A. Pahler, J.U. Peters, A. Petersen, E. Prinssen, A. Ricci, D. Rueher, M. Rueher, M. Schneider, P. Spurr, T. Stoll, D. Tannler, J. Wichmann, R.H. Porter, J.G. Wettstein, L. Lindemann, Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1Himidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases, J. Med. Chem. 58 (3) (2015) 1358– 1371, http://dx.doi.org/10.1021/jm501642c. [31] H.H. Nickols, J.P. Yuh, K.J. Gregory, R.D. Morrison, B.S. Bates, S.R. Stauffer, K.A. Emmitte, M. Bubser, W. Peng, M.T. Nedelcovych, A. Thompson, X. Lv, Z. Xiang, J. S. Daniels, C.M. Niswender, C.W. Lindsley, C.K. Jones, P.J. Conn, VU0477573: Partial negative allosteric modulator of the subtype 5 metabotropic glutamate receptor with in vivo efficacy, J. Pharmacol. Exp. Ther. 356 (1) (2016) 123–136, http://dx.doi.org/10.1124/jpet.115.226597.
69
[32] L. Zhang, G. Balan, G. Barreiro, B.P. Boscoe, L.K. Chenard, J. Cianfrogna, M.M. Claffey, L. Chen, K.J. Coffman, S.E. Drozda, J.R. Dunetz, K.R. Fonseca, P. Galatsis, S. Grimwood, J.T. Lazzaro, J.Y. Mancuso, E.L. Miller, M.R. Reese, B.N. Rogers, I. Sakurada, M. Skaddan, D.L. Smith, A.F. Stepan, P. Trapa, J.B. Tuttle, P.R. Verhoest, D.P. Walker, A.S. Wright, M.M. Zaleska, K. Zasadny, C.L. Shaffer, Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyra zine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, J. Med. Chem. 57 (3) (2014) 861–877, http://dx. doi.org/10.1021/jm401622k. [33] C.M. Tanner, Advances in environmental epidemiology, Mov. Disord. 25 (Suppl 1) (2010) S58–S62, http://dx.doi.org/10.1002/mds.22721. [34] H. Chen, X. Huang, X. Guo, R.B. Mailman, Y. Park, F. Kamel, D.M. Umbach, Q. Xu, A. Hollenbeck, A. Schatzkin, A. Blair, Smoking duration, intensity, and risk of Parkinson disease, Neurology 74 (11) (2010) 878–884, http://dx.doi.org/ 10.1212/WNL.0b013e3181d55f38. [35] J.M. Gorell, B.A. Rybicki, C.C. Johnson, E.L. Peterson, Smoking and Parkinson’s disease: a dose-response relationship, Neurology 52 (1) (1999) 115–119. [36] E. Hellstrom-Lindahl, J.A. Court, Nicotinic acetylcholine receptors during prenatal development and brain pathology in human aging, Behav. Brain Res. 113 (1–2) (2000) 159–168. [37] E. Perry, C. Martin-Ruiz, M. Lee, M. Griffiths, M. Johnson, M. Piggott, V. Haroutunian, J.D. Buxbaum, J. Nasland, K. Davis, C. Gotti, F. Clementi, S. Tzartos, O. Cohen, H. Soreq, E. Jaros, R. Perry, C. Ballard, I. McKeith, J. Court, Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases, Eur. J. Pharmacol. 393 (1–3) (2000) 215–222. [38] K. Utsugisawa, Y. Nagane, H. Tohgi, M. Yoshimura, H. Ohba, Y. Genda, Changes with aging and ischemia in nicotinic acetylcholine receptor subunit alpha7 mRNA expression in postmortem human frontal cortex and putamen, Neurosci. Lett. 270 (3) (1999) 145–148. [39] R.T. Reid, M.N. Sabbagh, Effects of donepezil treatment on rat nicotinic acetylcholine receptor levels in vivo and in vitro, J. Alzheimers Dis. 5 (6) (2003) 429–436. [40] C.M. Hernandez, D.A. Gearhart, V. Parikh, E.J. Hohnadel, L.W. Davis, M.L. Middlemore, S.P. Warsi, J.L. Waller, A.V. Terry Jr., Comparison of galantamine and donepezil for effects on nerve growth factor, cholinergic markers, and memory performance in aged rats, J. Pharmacol. Exp. Ther. 316 (2) (2006) 679– 694, http://dx.doi.org/10.1124/jpet.105.093047. [41] N. Morin, V.A. Jourdain, M. Morissette, L. Gregoire, T. Di Paolo, Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys, Neuropharmacology 79 (2014) 688–706, http://dx.doi.org/10.1016/j.neuropharm.2014.01.014. [42] N. Morin, M. Morissette, L. Gregoire, T. Di Paolo, Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys, Prog. Neuropsychopharmacol. Biol. Psychiatry 56 (2015) 27–38, http://dx.doi.org/10.1016/j.pnpbp.2014.07.006. [43] N. Morin, M. Morissette, L. Gregoire, B. Gomez-Mancilla, F. Gasparini, T. Di Paolo, Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys, Neuropharmacology 73 (2013) 216–231, http://dx.doi. org/10.1016/j.neuropharm.2013.05.028. [44] N. Morin, M. Morissette, L. Gregoire, A. Rajput, A.H. Rajput, T. Di Paolo, Contribution of brain serotonin subtype 1B receptors in levodopa-induced motor complications, Neuropharmacology 99 (2015) 356–368, http://dx.doi. org/10.1016/j.neuropharm.2015.08.002. [45] J.K. Mai, J. Assheuer, G. Paxinos, Atlas of the Human Brain, Academic Press, 1997.
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Brain a7 nicotinic acetylcholine receptors in MPTP-lesioned monkeys and parkinsonian patients Marc Morissette b,1, Nicolas Morin a,b,1, Laurent Grégoire b, Alex Rajput c, Ali H. Rajput c, Thérèse Di Paolo a,b,⇑ a b c
Faculty of Pharmacy, Université Laval, Quebec City G1K 7P4, Canada Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City G1V 4G2, Canada Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK S7N 0W8, Canada
a r t i c l e
i n f o
Article history: Received 5 February 2016 Accepted 29 March 2016 Available online 30 March 2016 Keywords: a7 nicotinic acetylcholine receptor Parkinson’s disease L-DOPA-induced dyskinesia Human MPTP-lesioned monkey
a b s t r a c t L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson’s disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain a7 nACh receptors might be a potential therapeutic target for PD. This study used [125I]aBungarotoxin autoradiography to investigate a7 nACh receptors in LID in post-mortem brains from PD patients (n = 14) and control subjects (n = 11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n = 5), L-DOPA (n = 4) or L-DOPA + 2-methyl-6-(phenyle thynyl)pyridine (MPEP) (n = 5), and control monkeys (n = 4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [125I]a-Bungarotoxin specific binding to striatal and pallidal a7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA + MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [125I]a-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [125I]a-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [125I]a-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [125I]a-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal a7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD. Ó 2016 Elsevier Inc. All rights reserved.
1. Introduction
Abbreviations: AIMs, abnormal involuntary movements; BSA, bovine serum albumin; DA, dopamine; DL, dorsolateral; DM, dorsomedial; GP, globus pallidus; GPe, external globus pallidus; GPi, internal globus pallidus; Hepes, 2-[4-(2-hydrox yethyl)-1-piperazinyl] ethanesulfonic acid; KRH, Krebs-Ringer Hepes; L-DOPA, L3,4-dihydroxyphenylalanine; LID, L-DOPA-induced dyskinesias; mGlu, metabotropic glutamate; MPEP, 2-methyl-6-(phenylethynyl)pyridine; MPTP, 1-methyl-4-ph enyl-1,2,3,6-tetrahydropyridine; nACh, nicotinic acetylcholine; NAM, negative allosteric modulator; PD, Parkinson’s disease; VL, ventrolateral; VM, ventromedial. ⇑ Corresponding author at: Neuroscience Research Unit, Centre de recherche du CHU de Québec, 2705 Laurier Boulevard, Quebec, Qc G1V 4G2, Canada. E-mail addresses: [email protected] (M. Morissette), [email protected] (N. Morin), [email protected] (L. Grégoire), [email protected] (A. Rajput), [email protected] (A.H. Rajput), [email protected] (T. Di Paolo). 1 Marc Morissette and Nicolas Morin are co-first authors and have contributed equally to this manuscript. http://dx.doi.org/10.1016/j.bcp.2016.03.023 0006-2952/Ó 2016 Elsevier Inc. All rights reserved.
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is likely to increase due to the aging population [1]. The cardinal motor manifestations of PD, tremor, bradykinesia, and rigidity, are secondary to a loss of striatal dopamine (DA) due DA neuron death in the substantia nigra [2]. Following chronic treatment with L-DOPA, motor complications including L-DOPA-induced dyskinesias (LID) and wearing-off appear in most parkinsonian patients [3]. Decreasing the dose of L-DOPA can decrease LID but usually worsens PD symptoms [4] hence alternative approaches are needed to effectively treat advanced PD. Other neurotransmitters and neuromodulators, such as glutamate, serotonin and acetylcholine are also affected in PD [5]. Striatal cholinergic interneurons are indispensable in controlling striatal neuronal activity and extrapyramidal motor movement
M. Morissette et al. / Biochemical Pharmacology 109 (2016) 62–69
[6]. Evidence indicates that the imbalance between cholinergic and dopaminergic systems plays a fundamental role in PD movement abnormalities [7]. Moreover, the ability of nicotine and nicotinic acetylcholine (nACh) receptor agonists to alleviate LID in parkinsonian animal models supports a role for the cholinergic system in LID [8,9]. nACh receptors are located mainly presynaptically modulating synaptic activity by regulation of neurotransmitter release [10]. a7 nACh receptors are highly expressed at glutamatergic terminals in the striatum [11] and their activation stimulates release of glutamate from corticostriatal terminals [12]. Our hypothesis is that LID are associated with changes in a7 nACh receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri dine (MPTP)-lesioned monkey model of PD and human parkinsonian post-mortem brains. To our knowledge, no study reported the effect of a metabotropic glutamate (mGlu) 5 receptor negative allosteric modulator (NAM) on brain a7 nACh receptors in parkinsonian monkeys. Our objectives were thus 1- to investigate the long-term effect of the prototypal mGlu5 receptor NAM, 2-methy l-6-(phenylethynyl)pyridine (MPEP) with L-DOPA that reduced development of LID on basal ganglia a7 nACh receptors in MPTP monkeys and 2- to verify if changes in a7 nACh receptors are associated with development of motor complications in L-DOPAtreated parkinsonian patients. 2. Materials and methods
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2.4. Human subjects Samples from PD patients of this study were previously investigated [15]. The clinical profiles of patients, their LID and wearingoff were well documented [16]. Wearing-off was defined as a predictable decline in motor benefit at the end of the dose in a patient with a previously stable response [16]. Patients were divided into groups based on the development of motor complications. These groups were not statistically different with respect to sex, age of death, brain pH, age of PD onset, duration of PD, duration of LDOPA use, average daily dose of L-DOPA, cumulative L-DOPA dose, duration of follow-up, and age at L-DOPA initiation. Eleven control patients (2 women and 9 men) were also studied. Delay to autopsy of the control subjects was <24 h and was not different from the delays for PD patients. The age at death of control subjects was 68 ± 3 and PD patients 78 ± 2 years (p < 0.01). Information on the smoking status of the controls was not available except for one who was a non-smoker and another that smoked 15 years but quit 15 years before death. All PD patients without dyskinesias were non-smokers except one that smoked until the age of 62 and died at age 69. All dyskinetic PD patients were non-smokers except for one for whom this information was not available and another noted not to smoke terminally. Twelve of the 14 PD patients had received anticholinergic drugs, one that displayed no motor complications and the other with dyskinesias only [17].
2.1. Animals and treatments This experiment used 18 drug naive female ovariectomized monkeys (Macaca fascicularis) (aged 4.7–7.7 years; weight: 2.7– 4.2 kg; Covance Research Products, China) in agreement with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The Laval University committee for the protection of animals approved this study. This study complies with the ARRIVE guidelines and all efforts were made to minimize animal suffering, to reduce the number of animals used, and to utilize alternatives to in vivo techniques, if they were available. Motor behavior of these monkeys was previously reported [13]. One group of monkeys (n = 4) remained untreated and served as controls and the others were rendered parkinsonian with MPTP (Sigma–Aldrich Canada Ltd., Oakville, ON, Canada). Five MPTP monkeys received saline (saline MPTP group), while four others received one month daily oral treatment with L-DOPA/benserazide alone (100/25 mg; ProlopaÒ) (Hoffmann-La Roche limited, Mississauga, ON, Canada) and the five remaining animals received L-DOPA/benserazide (same dosage) and MPEP (10 mg/kg, Novartis Pharma AG, Basel, Switzerland). L-DOPA improved parkinsonian scores, this response was unaffected by adding MPEP [13]. The mean dyskinesia score increased over a month in both L-DOPA-treated groups, but significantly less in L-DOPA + MPEP-treated monkeys [13]. 2.2. Animal tissue preparation Animals were killed 24 h after their last dose of L-DOPA and brains stored at 80 °C. Brains were cut into 12-lm coronal sections on a cryostat ( 18 °C). The posterior striatum from levels A15–A18 [14] was investigated. Slices were thaw-mounted onto SuperFrost Plus slides (Brain Research Laboratories, Newton, MA) and stored at 80 °C until assayed. Brain tissues were also collected to measure the extent of the lesion. 2.3. Animal DA denervation assays DA contents were measured by HPLC [13]. The MPTP lesion led to a similar extensive 98–99% reduction of striatal DA contents of all MPTP monkeys of this experiment [13].
2.5. Autopsy and handling of brain material Autopsies of all human subjects confirmed the PD diagnosis and showed marked neuronal loss in the substantia nigra pars compacta, presence of Lewy body, and absence of other pathological changes that may account for parkinsonian symptoms [16]. 2.6. Measures of extent of dopamine denervation in human brain There was a marked decrease in DA ( 98.8%) contents in the putamen of all PD patients compared with controls and no difference among the subgroups of PD patients [15]. 2.7. Autoradiography of a7 nACh receptors [125I]a-Bungarotoxin (143.8 Ci/mmol: Perkin Elmer, Boston, MA, USA) autoradiography was used to label a7 nACh receptors as reported [18]. Brain sections were pre-incubated for 30 min in a Krebs-Ringer Hepes buffer (KRH buffer) containing 20 mM Hepes (2-[4-(2-hydroxyethyl)-1-piperazinyl] ethanesulfonic acid), 118 mM NaCl, 4.8 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, and 10 mM NaOH (all products are from Sigma–Aldrich Canada Ltd., Oakville, ON, Canada), pH 7.4. The slides were then incubated for 120 min at room temperature with 50 nM [125I]a-Bungarotoxin in KRH buffer containing 0.05% bovine serum albumin (BSA) (EDM Millipore, Etobicoke, ON, Canada). To determine nonspecific binding, 50 lM ( )Nicotine (Sigma, Oakville, ON, Canada) was added to four human and four monkey brain sections. Nonspecific binding was also estimated with a measure of a constant area outside the caudate–putamen for each brain slice. A region of the same dimension was measured on each section at the level of internal capsule for human and monkey sections; for monkeys, a region near the caudate in the white matter was measured when the space between the caudate and putamen was too small. After incubation, slides were washed three times for 20 min in 20 mM KRH buffer, pH 7.4 at 4 °C, then rinsed in distilled water at 4 °C and allowed to air-dry overnight. Sections were then exposed to [125I]-sensitive films (Kodak BIOMAX MR, USA) for 2 weeks at room
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temperature. Films were developed and autoradiograms were analyzed by densitometry. 2.8. Image, data and statistical analysis The intensity of autoradiograms was quantified with a Power Macintosh G4 connected to a video camera (XC-77; Sony) and a constant-illumination light table using computerized densitometry (NIH image v.1.63). A standard grayscale strip (Stouffer Graphic Arts Equipment Co. Inc., IN, USA) was used to generate a calibration curve for optical densities. Optical gray densities were transformed into nCi/mg of tissue equivalent using a standard curve generated with standard [125I]-strips (GE Healthcare Life Sciences, Mississauga, ON, Canada). For each brain regions investigated, 4 brain slices for each human and animal were used for autoradiographic analyses. Statistical comparison of monkey results was performed by a two-way analysis of variance with putamen and globus pallidus subregions and treatments as factors, followed by post-hoc pairwise comparisons with Fisher’s least significant difference test. The caudate nucleus of monkeys was small at the brain region investigated, hence it was not subdivided into subregions and the whole area was analyzed by a one-way analysis of variance with treatment as factor, followed by post-hoc pairwise comparisons with Fisher’s least significant difference test. Human results were analyzed by a one-way analysis of variance with treatment as factor, followed by post-hoc pairwise comparisons with Fisher’s least significant difference test. Non-specific binding, estimated from each brain slice or from other brain slices in the presence of ( ) Nicotine, was subtracted from total binding and was used to generate two estimates of [125I]a-Bungarotoxin specific binding. The statistical analysis of both these specific binding values gave similar statistical changes and only one is presented. First, control subjects (n = 10) were compared to all PD patients (n = 14). Second, controls were compared to PD patients without motor complications (n = 4), with dyskinesias only (n = 4), with wearing-off only (n = 3) and with dyskinesia + wearing-off (n = 3). A simple regression model was used to determine coefficients of correlation and the significance of the degree of linear
relationship between the mean dyskinesia scores of the MPTPlesioned monkeys (n = 14, from the last week of behavioral observations [13]) and specific binding values. A value of p < 0.05 was considered significant.
3. Results 3.1. [125I]a-Bungarotoxin specific binding in monkey brains Fig. 1 shows examples of [125I]a-Bungarotoxin binding in a control and MPTP monkeys compared to non-specific binding. [125I]a-Bungarotoxin specific binding increased in the caudate nucleus (effect of treatment: F3,14 = 17.03, p < 0.0001; Fig. 2A), putamen (effect of treatment: F3,14 = 20.64, p < 0.0001; subregion: F3,42 = 20.11, p < 0.0001; interaction: F9,42 = 4.34, p < 0.001; Fig. 2B) and GP (effect of treatment: F3,14 = 9.39, p < 0.01; subregion: F1,14 = 65.83, p < 0.0001; interaction: F3,14 = 7.39, p < 0.01; Fig. 2C) of L-DOPA-treated MPTP monkeys compared to controls as well as saline and L-DOPA + MPEP treated MPTP groups (+39%, +38% and +40% for caudate nucleus, +34%, +32% and +43% for putamen and +42%, +23% and +27% for GP vs. each group respectively). [125I]a-Bungarotoxin specific binding did not change in the L-DOPA + MPEP-treated MPTP group compared to controls and saline-treated MPTP monkeys in the caudate nucleus, putamen and GP. The mean dyskinesia scores of the MPTP monkeys (n = 14) correlated positively with their striatal and pallidal [125I]a-Bungarotoxin specific binding (Fig. 3). 3.2. [125I]a-Bungarotoxin specific binding in human brains Fig. 4 shows examples of [125I]a-Bungarotoxin binding in controls and PD patients as well as non-specific binding. As compared to control subjects, [125I]a-Bungarotoxin specific binding of PD patients increased significantly in the caudate nucleus (+49%; Fig. 5A; F1,24 = 11.87, p < 0.01) whereas no change was observed in putamen (Fig. 5A) and GP (data not shown).
Fig. 1. Examples of [125I]a-Bungarotoxin binding to brain a7 nicotinic acetylcholine receptors showing an elevation in dyskinetic L-DOPA treated monkeys compared to a control, a MPTP-lesioned monkeys treated with saline and L-DOPA + MPEP treatment. Non-specific binding in the presence of ( )Nicotine is also shown. Schematic of the brain and regions analyzed is also presented. DM, dorsomedial; VM, ventromedial; VL, ventrolateral; DL, dorsolateral; external (GPe) and internal (GPi) globus pallidus.
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Fig. 2. Autoradiography of monkey brain a7 nicotinic acetylcholine receptors showing an increase in this receptor in LID. [125I]a-Bungarotoxin specific binding in the caudate nucleus (A) and putamen (B) of control monkeys (n = 4), and MPTP-lesioned monkeys treated with saline (n = 5), L-DOPA (n = 4) and L-DOPA + MPEP (n = 5). (C) [125I]a-Bungarotoxin specific binding in the external (GPe) and internal (GPi) globus pallidus of these monkeys. Data are expressed as mean ± SEM. One hundred percent control values (fmol/mg of tissue) were for the caudate nucleus, 0.467; for the putamen, DM = 0.466, VM = 0.483, DL = 0.491, VL = 0.513; and for the GP, GPe = 0.479, GPi = 0.532. ***p < 0.001 and ****p < 0.0001 vs. control monkeys; ##p < 0.01 and ###p < 0.001 vs. MPTP + saline-treated monkeys; ++p < 0.01, +++p < 0.001 and ++++p < 0.0001 vs. MPTP + L-DOPA-treated monkeys. DM, dorsomedial; VM, ventromedial; VL, ventrolateral; DL, dorsolateral.
As compared to control subjects, [125I]a-Bungarotoxin specific binding increased in the caudate nucleus of PD patients without and with motor complications, including PD patients with dyskinesias only and with dyskinesia + wearing-off (+45%, +68% and +60% vs. control subjects respectively; Fig. 5B; F4,20 = 4.49, p < 0.05) whereas no increase was observed in PD patients with wearingoff only. [125I]a-Bungarotoxin specific binding of PD patients with wearing-off only were lower than PD patients with dyskinesia in the caudate nucleus ( 38%). In the putamen, as compared to control subjects and PD patients without motor complications, [125I]a-Bungarotoxin specific binding only increased in PD patients with motor complications with dyskinesias only (+23% and +21% respectively; Fig. 5B; F4,20 = 6.73, p < 0.01) whereas the specific binding decreased in PD patients with wearing-off only ( 25% and 26% respectively; Fig. 5B; F4,20 = 6.73, p < 0.01). Specific binding levels of PD patients with dyskinesia and wearing-off were unchanged compared to control subjects and PD patients without motor complications. [125I]a-Bungarotoxin specific binding levels were higher in PD patients with dyskinesias only compared to PD patients with wearing-off only and PD patients with dyskinesia and wearingoff (+64% and +48% respectively; Fig. 5B; F4,20 = 6.73, p < 0.01).
No change was observed between the different groups of humans in GPe and GPi (Fig. 5C). 4. Discussion The present results are the first to show in the putamen elevated a7 nACh receptor specific binding of dyskinetic PD patients and MPTP monkeys with LID. The dyskinesia scores of MPTP monkeys correlated positively with their a7 nACh receptor specific binding with the highest correlation in the putamen implicated in motor control. A chronic mGlu5 receptor NAM treatment reducing development of LID inhibited striatal and pallidal elevation of a7 nACh receptor specific binding. The nACh receptor modulation, including a7 nACh receptors, by their agonists is not straightforward with the assumption that an agonist will replace or augment the stimulation provided by the natural activator [19]. For most nACh receptor subtypes a primary effect of the prolonged presence of an agonist is to produce desensitization, decreasing the effect of the normal fluctuations in ACh signaling [20]. Hence, the increase in a7 nACh receptors in LID would benefit from an agonist treatment that would desensitize (decrease functional activity) this receptor. Behaviorally, the a7
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Fig. 3. Positive correlations between mean dyskinesia scores of these monkeys and their [125I]a-Bungarotoxin specific binding (shown in Fig. 2) in the caudate nucleus (A), putamen (B), GPe (C) and GPi (D); each point represents an individual monkey.
Fig. 4. Examples of [125I]a-Bungarotoxin binding autoradiography to a7 nicotinic acetylcholine receptors in brain sections of a post-mortem control subject and L-DOPAtreated parkinsonian patients showing an elevation with LID. Non-specific binding in the presence of ( )Nicotine is also shown. The schematic of the human basal ganglia sections showing, the caudate nucleus (caudate), putamen, GPe and GPi was adapted from the Atlas of the human brain [45].
nACh receptor selective partial agonist, AQW051, alleviates LID in MPTP monkeys with an extension of the duration of L-DOPA antiparkinsonian activity [21]. The a7 nACh receptor agonist ABT-107 also decreases LID in parkinsonian monkeys [22]. Moreover, Ro 61–8048 that antagonizes glutamate receptors and inhibits a7 nACh receptors reduces development of LID in MPTP monkeys [23] and its expression in already dyskinetic MPTP monkeys [24]. These findings support the contribution of a7 nACh receptors in LID and their targeting for a possible novel therapeutic
treatment. Moreover, a7 nACh receptor agonists display neuroprotective activity in animal models of PD [25–27]. Distribution of a7 nACh receptor in monkeys [28] and healthy subjects [29] shows binding in the putamen, the caudate nucleus and GP as reported in the present study. A MPTP regimen leading to symptomatic motor impairment in monkeys was reported to increase [125I]a-Bungarotoxin specific binding only in the dorsolateral putamen [18]. By contrast, these authors showed an increase in all subregions of the putamen in asymptomatic MPTP
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Fig. 5. Autoradiography of human brain a7 nicotinic acetylcholine receptors showing an increase in this receptor in LID. (A) [125I]a-Bungarotoxin specific binding to a7 nicotinic acetylcholine receptors in the caudate nucleus and putamen of post-mortem human brain tissue from controls (n = 10) compared to all parkinsonian subjects (n = 14). (B) [125I]a-Bungarotoxin specific binding in the caudate nucleus and putamen of post-mortem human brain tissue from controls (n = 10) compared to parkinsonian subjects with motor complications or not following L-DOPA therapy (n=4 without motor complications group: 3 non-smokers and 1 smoked until age 62 and died at 69; n = 4 for dyskinesias only group: 2 non-smokers, 1 did not smoke terminally and 1 not available; n = 3 for wearing-off only group: all non-smokers and n = 3 for wearing-off + dyskinesias group: all non-smokers). (C) [125I]a-Bungarotoxin specific binding in the GPe and GPi of these subjects. Data are expressed as mean ± SEM. One hundred percent control values (fmol/mg of tissue) were for the caudate nucleus = 0.102, putamen = 0.151, GPe = 0.124 and GPi = 0.107. *p < 0.05 and **p < 0.01 vs. controls; &p < 0.05 vs. PD patients with dyskinesia only; #p < 0.05 vs. PD patients without motor complications. PD, Parkinson’s disease.
monkeys suggesting that this increase may be part of a compensatory process to help maintain motor functions in the earliest stages of PD. Accordingly, our vehicle-treated MPTP monkeys modeling late stages of the disease did not show increased [125I] a-Bungarotoxin specific binding in the putamen. In relation to LID, the effect in MPTP monkeys of L-DOPA and MPEP treatments on a7 nACh receptors is not yet available for comparison with the present results. It is nevertheless important to investigate the effects of mGlu5 receptor NAMs on nACh receptors since they are the object of intense research for various CNS diseases [30–32]. Nor are there reports on brain a7 nACh receptors of PD patients
in relation to motor complications. However, epidemiological studies show a decrease in PD in smokers [33] with an overall 50% decline in the risk of PD in tobacco users [34,35]. There are no reports on [125I]a-Bungarotoxin specific binding in the caudate nucleus and putamen in relation to aging of the human brain. However, there are reports of generalized loss of different nicotinic receptor subtypes in aging in various brain areas but only after the 70th decade in the striatum [36,37]. Moreover, no change of a7 nicotinic acetylcholine receptor mRNA was observed in the putamen between the age of 22–80 years [38]. The differences of a7 nACh specific binding among the human subjects investigated is
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unlikely due to the younger age of the controls compared to the PD patients since their binding was similar in the putamen (Fig 5A) and GP (Fig 5C). In the caudate nucleus the difference between the controls and the PD patients is more likely related to their motor complication rather than the age difference as Fig 5B shows. The a7 nACh receptor changes observed in the human brain investigated were unlikely related to their tobacco use since differences were observed between PD patients in relation to their motor complications and most of these patients were non-smokers. Moreover, these receptor changes were unlikely related to anticholinergic drug use since differences were observed between PD patients in relation to their motor complications and only one PD patient without motor complications and one with dyskinesias only did not receive anticholinergic drugs [17]. In animal models of PD, no data are available on the effect of anticholinesterase inhibitors on striatal a7 nACh receptor binding; one report showed in intact rats, no effect of chronic donepezil treatment on striatal a7 nACh receptors [39] and a study showed no effect of a chronic treatment in aged rats of the anticholinesterase inhibitors galantamine or donepezil on ambulatory activity [40]. Furthermore, the receptor changes in PD patients in relation to LID were similar to those observed in MPTP monkeys with LID and the latter were of similar age, never exposed to tobacco and they were drug naive at the start of the experiment. The MPTP monkeys of this experiment never received non-dopaminergic drugs except for those that were administered MPEP. Nevertheless as this manuscript showed, as well as our previous studies of the brain of these animals, the LDOPA and MPEP treatment affected various neurotransmitters and neuromodulators [13,41–44]. The a7 nACh receptor changes observed in PD and MPTP monkeys treated with chronic L-DOPA are more likely associated with the development of dyskinesias rather than the chronic L-DOPA treatment per se since the cumulative dose of L-DOPA was similar in the PD patients with and without motor complications [17] and the MPTP monkeys received similar doses in the chronic L-DOPA than the L-DOPA + MPEP groups. In the putamen, we observed no change in a7 nACh receptors of PD patients with no motor complications and in saline-treated MPTP monkeys. In addition, in the putamen of PD patients with dyskinesias only and MPTP monkeys treated with L-DOPA that developed LID, a7 nACh receptor specific binding was elevated. Hence, both in PD patients and parkinsonian monkeys an increase in a7 nACh receptors was observed in the putamen supporting relevance of this animal model and the implication of these receptors in relation to LID. PD patients that developed wearing-off only did not have an increase in striatal and pallidal a7 nACh receptor specific binding suggesting that this motor complication does not involve this nicotinic receptor. PD patients with dyskinesias and wearing-off had reduced a7 nACh receptor specific binding in putamen but elevated values in the caudate nucleus. Moreover, PD patients with no motor complications had elevated a7 nACh receptor specific binding compared to controls in the caudate nucleus. More research is required to decipher these latter findings. No change of pallidal a7 nACh receptor specific binding was observed in PD patients associated with the disease or motor complications. Similarly, in monkeys the MPTP lesion did not change pallidal a7 nACh receptor specific binding whereas elevated values were observed in dyskinetic MPTP monkeys. More research is required to further investigate pallidal a7 nACh receptors in relation to dyskinesias. In conclusion, the present results show a consistent elevation of basal ganglia a7 nACh receptor specific binding in LID in PD patients as well as in a non-human primate model of PD supporting the relevance of targeting this receptor to treat dyskinesias.
Conflict of interest Authors have no conflict of interest concerning this study and have nothing to declare. Acknowledgements This work was supported by a grant from the Canadian Institutes of Health Research to TDP (MOP-114916). N.M. held a professional health care studentship from the Fonds de la recherche en santé du Québec (FRSQ). References [1] A. Siderowf, M. Stern, Update on Parkinson disease, Ann. Intern. Med. 138 (8) (2003) 651–658. [2] C.W. Olanow, M.B. Stern, K. Sethi, The scientific and clinical basis for the treatment of Parkinson disease (2009), Neurology 72 (21 Suppl. 4) (2009) S1– S136, http://dx.doi.org/10.1212/WNL.0b013e3181a1d44c. [3] G. Fabbrini, J.M. Brotchie, F. Grandas, M. Nomoto, C.G. Goetz, Levodopainduced dyskinesias, Mov. Disord. 22 (10) (2007) 1379–1389, http://dx.doi. org/10.1002/mds.21475. quiz 1523. [4] N.B. Mercuri, G. Bernardi, The ’magic’ of L-dopa: why is it the gold standard Parkinson’s disease therapy? Trends Pharmacol. Sci. 26 (7) (2005) 341–344, http://dx.doi.org/10.1016/j.tips.2005.05.002. [5] P. Huot, T.H. Johnston, J.B. Koprich, S.H. Fox, J.M. Brotchie, The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease, Pharmacol. Rev. 65 (1) (2013) 171–222, http://dx.doi.org/10.1124/pr.111.005678. [6] F.M. Zhou, C.J. Wilson, J.A. Dani, Cholinergic interneuron characteristics and nicotinic properties in the striatum, J. Neurobiol. 53 (4) (2002) 590–605, http:// dx.doi.org/10.1002/neu.10150. [7] S. Kaneko, T. Hikida, D. Watanabe, H. Ichinose, T. Nagatsu, R.J. Kreitman, I. Pastan, S. Nakanishi, Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function, Science 289 (5479) (2000) 633–637. [8] M. Quik, D. Zhang, M. McGregor, T. Bordia, Alpha7 nicotinic receptors as therapeutic targets for Parkinson’s disease, Biochem. Pharmacol. 97 (4) (2015) 399–407, http://dx.doi.org/10.1016/j.bcp.2015.06.014. [9] M. Quik, T. Bordia, D. Zhang, X.A. Perez, Nicotine and nicotinic receptor drugs: potential for Parkinson’s disease and drug-induced movement disorders, Int. Rev. Neurobiol. 124 (2015) 247–271, http://dx.doi.org/10.1016/bs. irn.2015.07.005. [10] S. Wonnacott, Presynaptic nicotinic ACh receptors, Trends Neurosci. 20 (2) (1997) 92–98. [11] G.G. Nomikos, B. Schilstrom, B.E. Hildebrand, G. Panagis, J. Grenhoff, T.H. Svensson, Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness, Behav. Brain Res. 113 (1–2) (2000) 97–103. [12] M. Marchi, F. Bergaglia, A. Pedrini, M. Raiteri, Study of the bidirectional transport of choline by blocking choline carriers from outside or inside brain nerve terminals, J. Neurosci. Res. 61 (5) (2000) 533–540. [13] N. Morin, L. Gregoire, M. Morissette, S. Desrayaud, B. Gomez-Mancilla, F. Gasparini, T. Di Paolo, MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates, Neuropharmacology 66 (2013) 355–364, http://dx.doi.org/10.1016/j.neuropharm.2012.07.036. [14] J. Szabo, W.M. Cowan, A stereotaxic atlas of the brain of the cynomolgus monkey (Macaca fascicularis), J. Comp. Neurol. 222 (2) (1984) 265–300, http:// dx.doi.org/10.1002/cne.902220208. [15] F. Calon, A.H. Rajput, O. Hornykiewicz, P.J. Bedard, T. Di Paolo, Levodopainduced motor complications are associated with alterations of glutamate receptors in Parkinson’s disease, Neurobiol. Dis. 14 (3) (2003) 404–416. [16] A.H. Rajput, M.E. Fenton, S. Birdi, R. Macaulay, D. George, B. Rozdilsky, L.C. Ang, A. Senthilselvan, O. Hornykiewicz, Clinical-pathological study of levodopa complications, Mov. Disord. 17 (2) (2002) 289–296. [17] F. Calon, M. Morissette, A.H. Rajput, O. Hornykiewicz, P.J. Bedard, T. Di Paolo, Changes of GABA receptors and dopamine turnover in the postmortem brains of parkinsonians with levodopa-induced motor complications, Mov. Disord. 18 (3) (2003) 241–253, http://dx.doi.org/10.1002/mds.10343. [18] J.M. Kulak, J.S. Schneider, Differences in alpha7 nicotinic acetylcholine receptor binding in motor symptomatic and asymptomatic MPTP-treated monkeys, Brain Res. 999 (2) (2004) 193–202, http://dx.doi.org/10.1016/j. brainres.2003.10.062. [19] D.K. Williams, J. Wang, R.L. Papke, Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations, Biochem. Pharmacol. 82 (8) (2011) 915–930, http://dx.doi.org/10.1016/j.bcp.2011.05.001. [20] M.R. Picciotto, N.A. Addy, Y.S. Mineur, D.H. Brunzell, It is not ‘‘either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood, Prog. Neurobiol. 84 (4) (2008) 329–342, http://dx.doi.org/10.1016/j. pneurobio.2007.12.005.
M. Morissette et al. / Biochemical Pharmacology 109 (2016) 62–69 [21] T. Di Paolo, L. Gregoire, D. Feuerbach, W. Elbast, M. Weiss, B. Gomez-Mancilla, AQW051, a novel and selective nicotinic acetylcholine receptor alpha7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of lDopa effects in parkinsonian monkeys, Parkinsonism Relat. Disord. 20 (11) (2014) 1119–1123, http://dx.doi.org/10.1016/j.parkreldis.2014.05.007. [22] D. Zhang, M. McGregor, M.W. Decker, M. Quik, The alpha7 nicotinic receptor agonist ABT-107 decreases L-Dopa-induced dyskinesias in parkinsonian monkeys, J. Pharmacol. Exp. Ther. 351 (1) (2014) 25–32, http://dx.doi.org/ 10.1124/jpet.114.216283. [23] L. Gregoire, A. Rassoulpour, P. Guidetti, P. Samadi, P.J. Bedard, E. Izzo, R. Schwarcz, T. Di Paolo, Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys, Behav. Brain Res. 186 (2) (2008) 161–167, http://dx.doi.org/10.1016/j. bbr.2007.08.007. [24] P. Samadi, L. Gregoire, A. Rassoulpour, P. Guidetti, E. Izzo, R. Schwarcz, P.J. Bedard, Effect of kynurenine 3-hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in Parkinsonian monkeys, Mov. Disord. 20 (7) (2005) 792–802, http://dx.doi.org/10.1002/mds.20596. [25] S. Suzuki, J. Kawamata, T. Matsushita, A. Matsumura, S. Hisahara, K. Takata, Y. Kitamura, W. Kem, S. Shimohama, 3-[(2,4-Dimethoxy)benzylidene]anabaseine dihydrochloride protects against 6-hydroxydopamine-induced parkinsonian neurodegeneration through alpha7 nicotinic acetylcholine receptor stimulation in rats, J. Neurosci. Res. 91 (3) (2013) 462–471, http:// dx.doi.org/10.1002/jnr.23160. [26] V. Stuckenholz, M. Bacher, M. Balzer-Geldsetzer, D. Alvarez-Fischer, W.H. Oertel, R.C. Dodel, C. Noelker, The alpha7 nAChR agonist PNU-282987 reduces inflammation and MPTP-induced nigral dopaminergic cell loss in mice, J. Parkinsons Dis. 3 (2) (2013) 161–172, http://dx.doi.org/10.3233/JPD-120157. [27] T. Bordia, M. McGregor, R.L. Papke, M.W. Decker, J.M. McIntosh, M. Quik, The alpha7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions, Exp. Neurol. 263 (2015) 277–284, http://dx.doi.org/10.1016/j.expneurol.2014.09.015. [28] A.G. Horti, Y. Gao, H. Kuwabara, Y. Wang, S. Abazyan, R.P. Yasuda, T. Tran, Y. Xiao, N. Sahibzada, D.P. Holt, K.J. Kellar, M.V. Pletnikov, M.G. Pomper, D.F. Wong, R.F. Dannals, 18F-ASEM, a radiolabeled antagonist for imaging the alpha7-nicotinic acetylcholine receptor with PET, J. Nucl. Med. 55 (4) (2014) 672–677, http://dx.doi.org/10.2967/jnumed.113.132068. [29] D.F. Wong, H. Kuwabara, M. Pomper, D.P. Holt, J.R. Brasic, N. George, B. Frolov, W. Willis, Y. Gao, H. Valentine, A. Nandi, L. Gapasin, R.F. Dannals, A.G. Horti, Human brain imaging of alpha7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancy, Mol. Imaging Biol. 16 (5) (2014) 730–738, http://dx.doi.org/10.1007/s11307-0140779-3. [30] G. Jaeschke, S. Kolczewski, W. Spooren, E. Vieira, N. Bitter-Stoll, P. Boissin, E. Borroni, B. Buttelmann, S. Ceccarelli, N. Clemann, B. David, C. Funk, W. Guba, A. Harrison, T. Hartung, M. Honer, J. Huwyler, M. Kuratli, U. Niederhauser, A. Pahler, J.U. Peters, A. Petersen, E. Prinssen, A. Ricci, D. Rueher, M. Rueher, M. Schneider, P. Spurr, T. Stoll, D. Tannler, J. Wichmann, R.H. Porter, J.G. Wettstein, L. Lindemann, Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1Himidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases, J. Med. Chem. 58 (3) (2015) 1358– 1371, http://dx.doi.org/10.1021/jm501642c. [31] H.H. Nickols, J.P. Yuh, K.J. Gregory, R.D. Morrison, B.S. Bates, S.R. Stauffer, K.A. Emmitte, M. Bubser, W. Peng, M.T. Nedelcovych, A. Thompson, X. Lv, Z. Xiang, J. S. Daniels, C.M. Niswender, C.W. Lindsley, C.K. Jones, P.J. Conn, VU0477573: Partial negative allosteric modulator of the subtype 5 metabotropic glutamate receptor with in vivo efficacy, J. Pharmacol. Exp. Ther. 356 (1) (2016) 123–136, http://dx.doi.org/10.1124/jpet.115.226597.
69
[32] L. Zhang, G. Balan, G. Barreiro, B.P. Boscoe, L.K. Chenard, J. Cianfrogna, M.M. Claffey, L. Chen, K.J. Coffman, S.E. Drozda, J.R. Dunetz, K.R. Fonseca, P. Galatsis, S. Grimwood, J.T. Lazzaro, J.Y. Mancuso, E.L. Miller, M.R. Reese, B.N. Rogers, I. Sakurada, M. Skaddan, D.L. Smith, A.F. Stepan, P. Trapa, J.B. Tuttle, P.R. Verhoest, D.P. Walker, A.S. Wright, M.M. Zaleska, K. Zasadny, C.L. Shaffer, Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyra zine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, J. Med. Chem. 57 (3) (2014) 861–877, http://dx. doi.org/10.1021/jm401622k. [33] C.M. Tanner, Advances in environmental epidemiology, Mov. Disord. 25 (Suppl 1) (2010) S58–S62, http://dx.doi.org/10.1002/mds.22721. [34] H. Chen, X. Huang, X. Guo, R.B. Mailman, Y. Park, F. Kamel, D.M. Umbach, Q. Xu, A. Hollenbeck, A. Schatzkin, A. Blair, Smoking duration, intensity, and risk of Parkinson disease, Neurology 74 (11) (2010) 878–884, http://dx.doi.org/ 10.1212/WNL.0b013e3181d55f38. [35] J.M. Gorell, B.A. Rybicki, C.C. Johnson, E.L. Peterson, Smoking and Parkinson’s disease: a dose-response relationship, Neurology 52 (1) (1999) 115–119. [36] E. Hellstrom-Lindahl, J.A. Court, Nicotinic acetylcholine receptors during prenatal development and brain pathology in human aging, Behav. Brain Res. 113 (1–2) (2000) 159–168. [37] E. Perry, C. Martin-Ruiz, M. Lee, M. Griffiths, M. Johnson, M. Piggott, V. Haroutunian, J.D. Buxbaum, J. Nasland, K. Davis, C. Gotti, F. Clementi, S. Tzartos, O. Cohen, H. Soreq, E. Jaros, R. Perry, C. Ballard, I. McKeith, J. Court, Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases, Eur. J. Pharmacol. 393 (1–3) (2000) 215–222. [38] K. Utsugisawa, Y. Nagane, H. Tohgi, M. Yoshimura, H. Ohba, Y. Genda, Changes with aging and ischemia in nicotinic acetylcholine receptor subunit alpha7 mRNA expression in postmortem human frontal cortex and putamen, Neurosci. Lett. 270 (3) (1999) 145–148. [39] R.T. Reid, M.N. Sabbagh, Effects of donepezil treatment on rat nicotinic acetylcholine receptor levels in vivo and in vitro, J. Alzheimers Dis. 5 (6) (2003) 429–436. [40] C.M. Hernandez, D.A. Gearhart, V. Parikh, E.J. Hohnadel, L.W. Davis, M.L. Middlemore, S.P. Warsi, J.L. Waller, A.V. Terry Jr., Comparison of galantamine and donepezil for effects on nerve growth factor, cholinergic markers, and memory performance in aged rats, J. Pharmacol. Exp. Ther. 316 (2) (2006) 679– 694, http://dx.doi.org/10.1124/jpet.105.093047. [41] N. Morin, V.A. Jourdain, M. Morissette, L. Gregoire, T. Di Paolo, Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys, Neuropharmacology 79 (2014) 688–706, http://dx.doi.org/10.1016/j.neuropharm.2014.01.014. [42] N. Morin, M. Morissette, L. Gregoire, T. Di Paolo, Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys, Prog. Neuropsychopharmacol. Biol. Psychiatry 56 (2015) 27–38, http://dx.doi.org/10.1016/j.pnpbp.2014.07.006. [43] N. Morin, M. Morissette, L. Gregoire, B. Gomez-Mancilla, F. Gasparini, T. Di Paolo, Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys, Neuropharmacology 73 (2013) 216–231, http://dx.doi. org/10.1016/j.neuropharm.2013.05.028. [44] N. Morin, M. Morissette, L. Gregoire, A. Rajput, A.H. Rajput, T. Di Paolo, Contribution of brain serotonin subtype 1B receptors in levodopa-induced motor complications, Neuropharmacology 99 (2015) 356–368, http://dx.doi. org/10.1016/j.neuropharm.2015.08.002. [45] J.K. Mai, J. Assheuer, G. Paxinos, Atlas of the Human Brain, Academic Press, 1997.