2B receptor antagonist in rats with unilateral 6-OHDA + parafascicular lesions

Brain Research Bulletin 78 (2009) 91–96

Contents lists available at ScienceDirect

Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull

Short communication

Behavioural effects of a selective NMDA NR1A/2B receptor antagonist in rats with unilateral 6-OHDA + parafascicular lesions L. Truong a , H.N. Allbutt a , M.J. Coster b , M. Kassiou b,c,d , J.M. Henderson a,∗ a

Department of Pharmacology, Bosch Building, Bosch Institute & School of Medical Sciences, University of Sydney, NSW 2006, Australia School of Chemistry, University of Sydney, NSW 2006, Australia c Discipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia d Brain and Mind Research Institute, University of Sydney, NSW 2050, Australia b

a r t i c l e

i n f o

Article history: Available online 11 November 2008 Keywords: Parkinson’s disease 6-Hydroxydopamine Centromedian–parafascicular complex NMDA antagonist Rat behavioural analysis l-dopa

a b s t r a c t Experimental lesions involving the parafascicular (Pf) nucleus and medial forebrain bundle (MFB) may model to some extent the pathological loss of glutamatergic neurons from the centromedian–parafascicular (CM–Pf) complex and nigral dopaminergic cell loss observed clinically at post-mortem in Parkinson’s disease (PD) cases. Our study investigated whether there were alterations in symptomatology in such rats with unilateral 6-OHDA + Pf lesions after treatment with either a selective NR1A/NR2B NMDA antagonist and/or l-dopa. Rats were given dual surgery to the MFB with 6-hydroxydopamine (6-OHDA) and Pf with N-methyl-d-aspartate (NMDA). (i) An NR1A/NR2B selective NMDA antagonist (BZAD-01; 10 mg/kg), (ii) l-dopa (25 mg/kg), (iii) BZAD-01 + l-dopa (10 mg/kg; 25 mg/kg) or (iv) vehicle solution were administered for 6 weeks, during which behavioural testing was performed. BZAD-01 improved postural asymmetry in the first month as well as apomorphine-induced rotation. The latter was also improved by l-dopa in this model. These data support the use of selective NR1/NR2B NMDA antagonists in the therapeutics of PD. © 2008 Elsevier Inc. All rights reserved.

1. Introduction The degeneration of the dopaminergic substantia nigra pars compacta (SNpc) with Lewy body formation is considered as the main pathological hallmark of PD. However, post-mortem studies of human PD cases indicate that glutamatergic neurons in the centromedian–parafascicular (CM–Pf) complex degenerate by approximately 40% [8]. Whilst bradykinesia, rigidity and resting tremor improve after dopamine-replacement therapy with l-dopa, postural and locomotor deficits remain refractory and motor complications arise. It is conceivable that involvement of non-dopaminergic nuclei such as the CM–Pf may contribute to some of these features. In rodents, the lateral Pf is homologous to the primate CM, whilst the medial Pf corresponds to Pf proper in primates [16]. For ease we simply refer to the rodent complex as Pf in this article. CM–Pf has extensive basal ganglia connectivity and constitutes the major source of thalamostriatal projection and is therefore in a position to modulate basal ganglia output [10,15,16]. The extensive con-

∗ Corresponding author. Tel.: +61 2 9036 9408; fax: +61 2 9351 3868. E-mail address: [email protected] (J.M. Henderson). 0361-9230/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2008.10.004

nectivity of CM–Pf is reviewed in this special issue by Smith and co-workers as well as Sadikot and Rymer. In animals, striatal dopamine depletion is associated with overactivation of glutamatergic N-methyl-d-aspartate (NMDA) receptors [13]. The striatal projection neurons are enriched in NMDA receptors composed of NR1/NR2B subunits [12]. In PD, additional partial degeneration of the CM–Pf would reduce glutamatergic thalamostriatal innervation. As a compensation for reduced input after such lesions, there could be enhanced striatal glutamatergic transmission. In unilateral 6-OHDA lesioned rats exhibiting partial Pf degeneration, remaining Pf neurons innervating the striatum showed increased in vesicular glutamate transporter 2 and metabolic activity (increased cytochrome oxidase subunit 1 mRNA expression), which the authors suggested represented a compensatory increase in thalamostriatal activation [2]. There may also be altered expression or increased sensitivity of glutamate receptors. Of relevance, a recent post-mortem study demonstrated increased binding of [3 H]Ro 25-6981 to striatal glutamatergic NMDA receptors containing NR1A/NR2B subunits which was associated with a history of motor complications in PD cases [4]. In preclinical studies, NMDA NR1A/NR2B receptor antagonists such as Ro 25-6981 and CP-101,606 have improved parkinsonian symptoms or l-dopa induced dyskinesias [12,13,17,19].

92

L. Truong et al. / Brain Research Bulletin 78 (2009) 91–96

However, neurotoxicity and psychomimetic actions can occur as a result of NMDA antagonists binding to other receptors. We have tested another compound, BZAD-01 (4-(trifluoromethoxy)-N-(2(trifluoromethyl)benzyl)-benzamidine) and found a reduction in l-dopa potentiation of apomorphine-induced rotational asymmetry in the unilateral 6-OHDA model [18]. BZAD-01 has the advantage of high affinity for the NMDA NR2B subunit (Ki = 72 nM) and high oral bioavailability [5]. This study therefore evaluated the efficacy of the BZAD-01 in a rat model of PD, which combined both 6-OHDA-induced SNpc and NMDA-induced Pf lesions. 2. Methods All procedures were carried out under institutional ethical approval and in accordance with National Health and Medical Research Council Guidelines on Use and Care of Animals in Research and the European Communities Council Directive of 24 November 1986 (86/609/EEC). Forty Sprague–Dawley female rats underwent baseline behavioural assessments, were retested fortnightly for a month after surgery, then drug treatments were commenced (approximately 6 weeks post-operatively) and testing resumed at fortnightly intervals for a further 6 weeks.

2.5. Cellular quantification Bilateral quantification of nigral dopaminergic cells in multiple serial sections was done using stereology as previously described for the unilateral 6-OHDA model [9,18]. The percentage cell loss of TH immunoreactive cells (TH+ve ) relative to that found in sham-operated animals was calculated. For Pf cell quantification, sections were placed under a microscope and images taken digitally and cells counted using the IM1000 software (Leitz, Germany). Cell morphology (size and shape) were used to assist regional delineation. The total numbers of NeuN-stained cells (NeuN+ve cells) in Pf were quantified in serial sections [9] and % cell loss was calculated in a similar manner to TH neurons. Since cellular quantification of Pf alone did not account for toxin spread, the extent of lesioning was tabulated with reference to the rat atlas [14] (Fig. 1 and Table 1). Rats with poorly targeted MFB lesions or <90% cell loss in the ipsilateral nigra were rejected from analysis. Those with evidence of mistargeting or <25% involvement of the Pf were also excluded. Groups were further matched for degree of involvement of the contralateral SNpc. 2.6. Statistical analysis Statview (version 5.0, SAS Institute, Cary, NC) was used for statistical analysis. Cell counts were analysed via analysis of variance (ANOVA). Behavioural variables

2.1. Surgery Rats were anaesthetised under isoflurane gas (3% induction and 1.5% maintenance) and given medial forebrain bundle lesions (MFB; AP −4.4, L ±1.1, both from bregma, V −8.0 mm from dura) using 4 ␮g/␮L 6-OHDA.HBr infused at a rate of 1 ␮L/min for 4 min [9,18]. During the same procedure, the rats then received a further 1 ␮L of 0.12 M NMDA (0.5 ␮L/min for 2 min) into Pf (AP −4.16, L ±1.3, both from bregma, V −6.0 mm from dura) [9]. Prophylactic buprenorphine (0.05 mg/kg s.c.) was given for pain relief, the wound was sutured and midazolam (5.0 mg/kg i.p. Midazolam hydrochloride, Pharmacia & Upjohn, Australia) given as necessary to control seizures. 2.2. Drug treatments Rats were randomised into four groups of 10 rats. Similar to our study in 6-OHDA lesioned rats [18], groups received either (1) vehicle, (2) BZAD-01 (10 mg/(kg day)), (3) BZAD-01 (10 mg/(kg day)) + l-dopa (25 mg/(kg day)) or (4) ldopa (25 mg/(kg day)). The active drugs were administered in 0.1% ascorbate + 5% sucrose solution (which comprised vehicle solution). See [18] for further details of solutions. Despite the limitations of oral dosing in drinking water [18], >90% of each solution was taken daily. 2.3. Behavioural assessments 2.3.1. Apomorphine rotation The rat was placed in a hemispheric bowl after 0.2 mg/kg apomorphine s.c. and the number and direction of turns made in a half hour period was recorded. This was performed at the end of drug treatment prior to sacrifice [9,18]. 2.3.2. Curling This task measured body axis bias and was performed five times per test week [9,18]. It was recorded as neutral (<10◦ bias in either direction), mild, moderate or severe, and the side of the deviation noted. The net bias was then calculated. 2.3.3. Beam run A stopwatch was used to record the time taken by the rat to cross a narrow 1 m length beam, elevated approximately 80 cm from the floor [1,18]. This was also performed five times on each test week and results were averaged. 2.4. Histology and immunohistochemistry Rats were perfused transcardially, the brains removed, cryoprotected and cut with a freezing microtome into 40 ␮m thick coronal sections as previously described [18]. Every fifth section was collected free floating for tyrosine hydroxylase (TH) immunohistochemistry (mouse anti-TH antibody 1:2000 dilution) and parallel series were used for Cresyl violet staining or NeuN immunohistochemistry (mouse anti-NeuN antibody NeuN; MAB 377, Chemicon International; 1:2000 dilution) [9,18]. In order to obtain similar staining intensities, all brain sections were processed simultaneously and incubations times were kept rigorously constant from specimen to specimen. TH or NeuN sections were then transferred onto gelatinised slides after diaminobenzidine chromogen reaction, air dried, dehydrated and cover slipped with mounting medium.

Fig. 1. Camera lucida diagram indicating extent of a small (light grey on left) vs. large (dark grey on right) lesion affecting the Pf and neighbouring regions.

L. Truong et al. / Brain Research Bulletin 78 (2009) 91–96

93

Table 1 Extent of thalamic lesions. Rat #

Group

CM–Pf topography

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Control Control Control Control Control Control BZAD BZAD BZAD BZAD l-dopa + BZAD l-dopa + BZAD l-dopa + BZAD l-dopa l-dopa l-dopa l-dopa

Lateral Posterior Anterior Lateral Posterolateral Lateral Anterior Lateral Posterior Posterior Lateral Posterior Posterior Posterior Posterior Posterior Lateral

LH

Po X X

X X X

X X X X X X

X

X

X

X

Sub Pf

AP/CL/LP

X X

+/−/−

VL, VPM

X X X

+/−/+

X X

X X

Other

+/−/+ +/−/− −/+/+ −/+/− −/+/+ +/−/− +/−/− −/+/− PCN, VH +/−/− +/−/+ +/+/+ +/−/− +/−/−

MD, PH, PV MM, SCP, VH VPL/VPM MD MD, VM, PC PC, SCP SCP, PCN MD, MM, SCP PC PC, VPM/VPLy VPM/VPL, SCP MG, PC

Abbreviations—AP: anterior pretectal nucleus; LH: lateral habenula; LP: lateral posterior nucleus; MD: mediodorsal nucleus; MG: medial geniculate; MM: medial mammillary nucleus; PC: paracentral nucleus; PCN: precommisural nucleus; PH: posterior hypothalamus; Po: posterior thalamus; PV: paraventricular nucleus; SCP: superior cerebellar peduncle; Sub Pf: subparafascicular nucleus; VH: ventral hippocampus; VL: ventrolateral thalamic nucleus; VPM/VPL: ventroposteromedial and ventroposterolateral thalamic nuclei. (+) involved; (−) not involved.

measured over time were analysed via two-way repeated measures ANOVA [9,18]. Post hoc group differences were assessed via Fischer’s progressive least significant differences test [9,18]. Final groups consisted of (1) vehicle (n = 6), (2) BZAD-01 (n = 4), (3) BZAD-01 + l-dopa (n = 3) or (4) l-dopa (n = 4).

as fast as after surgery, but this was not significant compared to vehicle-treated rats. Rats given combined treatment showed a trend towards improved performance vs. vehicle-treated rats, but this was not dissimilar to their post-operative performance (ANOVA

3. Results 3.1. Lesions Rats with unilateral 6-OHDA + Pf lesions had at least 90% dopaminergic nigral cell loss on the operated side (Fig. 2A). However, there was also an average of 50% dopaminergic cell loss in the unoperated nigra (Fig. 2B). Pf cell loss averaged 36% (range 25–66%) and was not significantly different across groups. Most lesions were located in the lateral or posterior Pf (Fig. 3) and spread to involve nearby structures such as the posterior thalamus, lateral posterior thalamic nucleus, precentral and anterior pretectal nuclei (Fig. 1 and Table 1). 3.2. Behavioural observations 3.2.1. Apomorphine rotation Rats with unilateral 6-OHDA + Pf lesions rotated vigorously after apomorphine (averaging 317 turns per half hour), not dissimilar to that observed in 6-OHDA lesioned rats [9]. However, when chronically exposed to either l-dopa or BZAD-01, the rotation was substantially reduced by >90%. Rats given both l-dopa + BZAD-01 did not experience as marked a reduction of rotation (approximately 25%) compared to either drug when given as a monotherapy (Fig. 4A). 3.2.2. Curling Prior to surgery there was no significant body axis bias. 6OHDA + Pf lesioned rats exhibited a significant curling bias towards the ipsilateral (lesioned) side. This was significantly reduced by BZAD-01 during the first month of drug treatment but the effect started to wear off at 6 weeks (Fig. 4B). 3.2.3. Beam run 6-OHDA + Pf lesioned rats were slower to cross the beam than after the baseline. BZAD-01 treated rats crossed the beam twice

Fig. 2. Cellular quantification of estimated total number of TH+ve neurons in substantia nigra on (A) ipsilateral (lesioned) side and (B) contralateral (non-lesioned) sides. On the lesioned side there was >90% cell loss after 6-OHDA + Pf lesions when compared to five rats with sham surgery from another study (ANOVA F = 112.425, P < 0.0001; post hoc ***P < 0.0001 for all lesioned groups vs. sham surgery rats). Interestingly, there was on average 50% loss of TH+ve neurons on the contralateral side in unilateral 6-OHDA + Pf lesioned rats (ANOVA F = 8.486, P = 0.0006), a finding which was common to rats in all treatment groups (post hoc **P < 0.0005 for all lesioned vs. sham surgery groups).

94

L. Truong et al. / Brain Research Bulletin 78 (2009) 91–96

F = 334.397, P < 0.0001, post hoc P = 0.0776 for l-dopa + BZAD-01 vs. vehicle treated rats only, all other comparisons non-significant; data therefore not shown). 4. Discussion Rats with dual 6-OHDA + Pf lesions rotated markedly in response to apomorphine. However, when pretreated with either BZAD-01 or l-dopa, rotation was substantially reduced. Rats given BZAD-01 also exhibited a significant reduction in ipsilateral curling bias during the first month of treatment. 4.1. Pf lesions and nigral cell loss

Fig. 3. Cresyl violet stained section from a rat illustrating a large thalamic lesion. Comparing the intact side (left) with the lesioned side (right) it can be seen that whilst the excitotoxic lesion is involves Pf there is extension to neighbouring thalamic nuclei. Fr = fasciculus retroflexus. Scale bar = 0.5 mm.

Fig. 4. (A) Apomorphine rotation. Vehicle-treated rats with unilateral 6-OHDA + Pf lesions rotated vigourously, whilst those treated with either BZAD-01 or l-dopa experienced very little rotational asymmetry (ANOVA F = 492.987, P < 0.0001, post hoc ***P < 0.0001 for either monotherapy compared to vehicle treated rats. Rats given combined therapy also rotated less (post hoc combined therapy vs. vehicle ***P < 0.0001), but the effect was not as great as for either monotherapy (post hoc combined therapy vs. either BZAD-01 or l-dopa ˆ P < 0.0001). (B) Curling (body axis bias). Rats with unilateral 6-OHDA + Pf lesions developed a severe ipsilateral curling bias (approximately 4 on a scale of 0–5; ANOVA F = 14.577, P < 0.0001). After drug treatment, the BZAD-01 treated rats exhibited a marked reduction in curling bias which was significantly different to both vehicle treated rats (*P = 0.0195) and l-dopa treated rats (*P = 0.0160), but not combined treatment (P = 0.0567). This improvement was most evident in the first month (Postdrug 1, similar data pooled for weeks 2 and 4) and started to wear off at 6 weeks (Postdrug 2).

Rats with 6-OHDA + Pf lesions exhibited >90% loss of TH+ve nigral neurons on the lesioned side, but of interest there was also approximately 50% loss of nigral neurons on the non-lesioned side. We have not seen significant bilateral cell loss in rats given unilateral 6-OHDA lesions alone. We do not believe this is a loss of TH phenotype with cellular preservation since neuronal loss was also evident on cresyl violet staining. The main communality between thalamic lesioned rats was that all had involvement of the Pf with the degree of cell loss being comparable to that seen in PD [8]. However, a limitation of such excitotoxic lesioning studies in rodents that must be borne in mind is that the involvement of Pf is not isolated, and other nuclei, not implicated in PD, are involved due to lesion spread. Also, the selective loss of parvalbumin-positive neurons in Pf is not observed [8]. The thalamic lesions targeted the lateral or posterior Pf in most rats but also affected other neighbouring thalamic nuclei to variable extents. The lesion spread was comparable to another study of cellular and metabolic effects of ibotenic acid-induced Pf lesions which were also found to spread to the centrolateral, paracentral, mediodorsal and posterior thalamic nuclei [3]. In our study, some rats also had extension into ventral thalamic nuclei, however since there were no differences in behaviour on all three tests compared to those without such involvement, they were retained for analysis. In a previous study of Pf and nigral lesions we did not find a marked degeneration of the nigra on the non-operated side [9]. A major difference between the two studies was that we formerly made the 6-OHDA lesions first, allowed 7 weeks recovery, then made Pf lesions (on the same side) and sacrificed the rats 6 weeks later. Perhaps the “double-hit” involving both the nigra and Pf in the same operation in this study may have resulted in a subtle retrograde degenerative process on the opposite side which became evident at post-mortem since there was a 3-month period from the time of surgery in which this process could evolve. Conversely, other authors have identified Pf degeneration after nigral lesions suggesting that the SNpc degeneration triggers thalamic cell loss via a retrograde process [2]. Mice with 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced SNpc degeneration also exhibited Pf degeneration [6]. A rat model of striatonigral degeneration involving intrastriatal 1-methyl-4phenylpyridinium ion (MPP+ ) induced loss of striatal neurons showed retrograde degeneration in both SNpc and Pf (with 38% reduction in neuronal density in Pf) [7]. In our post-mortem study of PD patients, whilst the number of cases was small, we found a similar degree of cell loss in CM–Pf in mildly affected patients compared to those with more advanced disease, suggesting that thalamic degeneration is an early, rather than a late feature of PD [8]. Overall these combined observations pose the question of when exactly does thalamic degeneration occur in relation to SNpc degeneration in PD? Resolving this issue will be of great importance in furthering our understanding of the pathophysiological processes at play in PD.

L. Truong et al. / Brain Research Bulletin 78 (2009) 91–96

4.2. Effects of drug treatments on apomorphine rotation The 6-OHDA + Pf lesioned rats in the present study rotated vigourously in response to apomorphine, similar to that observed previously in rats with similar lesions and in 6-OHDA lesioned rats [8]. These data suggest that additional Pf lesions do not prevent the acute rotational response to a single apomorphine challenge [9]. The reduction in apomorphine-induced rotation in the presence of BZAD-01 or l-dopa pre-treatment in this model was different to the unilateral 6-OHDA model, where l-dopa pre-treatment increased apomorphine rotation [18]. Furthermore, BZAD-01 coadministration prevented the l-dopa-induced rise in apomorphine rotation in unilateral 6-OHDA lesioned rats [18]. These results imply that Pf lesions modify the response to drugs given chronically. It this model it is possible that there is a down-regulation or decrease in supersensitivity of striatal DA receptors (after l-dopa) and NMDA receptors (after BZAD-01). However, the effect on rotation was less pronounced when the two drugs were given together which could be a dose-related problem. For comparability purposes, we chose 10 mg/kg BZAD-01 in this study since this dose affected ldopa enhanced apomorphine rotation in the 6-OHDA model [18]. We have not trialed lower doses of BZAD-01 and/or l-dopa in this model. There is evidence that smaller doses of l-dopa and NMDA antagonists are required when combined than when administered as monotherapy in order to exert antiparkinsonian effects due to synergistic drug interactions. One study found that the dose of the NMDA antagonist (CP-101,606) needed to be reduced 20-fold when combined with a standard dose of l-dopa [17]. Recent work found that Pf lesions appear to counteract changes associated with unilateral 6-OHDA lesions. Specifically, Pf lesions reduced elevated mRNA levels for striatal enkephalin and GAD67, for GAD67 in both the globus pallidus and entopeduncular nucleus and decreased metabolic overactivity of the STN (as measured by cytochrome oxidase subunit 1) [3]. It is possible that such mechanisms downstream of the striatum may contribute to the differential behavioural observations (i.e. on rotation) in our studies examining the effects of l-dopa and/or BZAD-01 in the two different animal models of PD [18]. However, our other behavioural data (i.e. curling, beam run speed) did not indicate less parkinsonism in rats with combined 6-OHDA + Pf lesions when compared to those with 6-OHDA lesions alone [9,18]. 4.3. Other behavioural parameters In previous work, 6-OHDA lesions induced head positioning and curling towards the ipsilateral side, slower crossing speed on the beam task, slower speed to retrieve a food reward and to start grooming and the rats exhibited increased piloerection [9]. Pf lesions had no effect on body axis if small and located in posterior Pf [9], but large lesions involving anterior Pf induced contralateral curling bias and slowed speed of retrieval of a food reward [9]. Whilst Pf lesions worsened piloerection, we did not, however, previously examine beam performance [9]. In the present study, the improved curling response was most prominent during the first month of BZAD-01 and appeared to wear off at 6 weeks. This suggests some improvement of postural instability in the short-term. Theoretically, either compensatory supersensitisation or overexpression of NR2B-containing NMDA receptors in the striatum may occur after thalamostriatal deafferentation resulting from Pf lesions. BZAD-01 could block glutamatergic overactivity involving striatal NR1/2B NMDA receptors in this model. This could in turn, reduce the excessive glutamatergic STN drive to basal ganglia output nuclei (GPi and SNr) thus reducing the curling bias. It is possible other complex changes within the basal ganglia occurred which counteracted this effect long-term.

95

Whilst there was no significant effect of BZAD-01 on beam run performance in the present study, a trend towards improved crossing speed was observed in the unilateral 6-OHDA lesion model [18]. However, interpretation of these results is hampered by small sample sizes. In other recent work, dramatic improvements in both curling and beam run performance occurred when 10 mg/kg BZAD01 was administered prior to unilateral 6-OHDA lesions [11]. This reflected a marked reduction in dopaminergic cell loss in BZAD01 treated compared to vehicle treated rats (47% vs. 92% cell loss, respectively) [11]. It is currently unclear whether BZAD-01 is neuroprotective against Pf lesions. 4.4. Conclusion Pf lesions may influence the development of nigral lesions on the non-lesioned side. BZAD-01 or l-dopa pre-treatment reduced apomorphine rotation in 6-OHDA + Pf lesioned rats. BZAD-01 also transiently improved curling. Further studies are required to ascertain the potential utility of BZAD-01 and related compounds in PD therapeutics. Acknowledgements The authors would like to acknowledge the support of Australian Rotary Health and Rotary Liverpool West. We appreciate the technical assistance of Dr Jane Radford in the Department of Pathology, University of Sydney and would also like to thank Julian Henderson and Christina Lui for assistance with figure work. References [1] H.N. Allbutt, J.M. Henderson, Use of the narrow beam test in the rat, 6hydroxydopamine model of Parkinson’s disease, J. Neurosci. Methods 159 (2007) 195–202. [2] M.S. Aymerich, P. Barroso-Chinea, M. Perez-Manso, A.M. Munoz-Patino, M. Moreno-Igoa, T. Gonzalez-Hernandez, J.L. Lanciego, Consequences of unilateral nigrostriatal denervation on the thalamostriatal pathway in rats, Eur. J. Neurosci. 23 (2006) 2099–2108. [3] J.J. Bacci, P. Kachidian, L. Kerkerian-Le Goff, P. Salin, Intralaminar thalamic nuclei lesions: widespread impact on dopamine denervation-mediated cellular defects in the rat basal ganglia, J. Neuropathol. Exp. Neurol. 63 (2004) 20–31. [4] F. Calon, A.H. Rajput, O. Hornykiewicz, P.J. Bedard, T. Di Paolo, Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson’s disease, Neurobiol. Dis. 14 (2003) 404–416. [5] C.F. Claiborne, J.A. McCauley, B.E. Libby, N.R. Curtis, H.J. Diggle, J.J. Kulagowski, S.R. Michelson, K.D. Anderson, D.A. Claremon, R.M. Freidinger, R.A. Bednar, S.D. Mosser, S.L. Gaul, T.M. Connolly, C.L. Condra, B. Bednar, G.L. Stump, J.J. Lynch, A. Macaulay, K.A. Wafford, K.S. Koblan, N.J. Liverton, Orally efficacious NR2B-selective NMDA receptor antagonists, Bioorg. Med. Chem. Lett. 13 (2003) 697–700. [6] T.E. Freyaldenhoven, S.F. Ali, L.C. Schmued, Systemic administration of MPTP induced thalamic neuronal degeneration in mice, Brain Res. 759 (1997) 9–17. [7] I. Ghorayeb, P.O. Fernagut, L. Hervier, B. Labattu, B. Bioulac, F. Tison, A ‘single toxin-double lesion’ rat model of striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis, Neuroscience 115 (2002) 533–546. [8] J.M. Henderson, K. Carpenter, H. Cartwright, G.M. Halliday, Degeneration of the centre median-parafascicular complex in Parkinson’s disease, Ann. Neurol. 47 (2000) 345–352. [9] J.M. Henderson, S.B. Schleimer, H.N. Allbutt, V. Dabholkar, D. Abela, J. Jovic, M. Quinlivan, Behavioural effects of parafascicular thalamic lesions in an animal model of parkinsonism, Behav. Brain Res. 162 (2005) 222–232. [10] J.L. Lanciego, N. Gonzalo, M. Castle, C. Sanchez-Escobar, M.S. Aymerich, J.A. Obeso, Thalamic innervation of striatal and subthalamic neurons projecting to the rat entopeduncular nucleus, Eur. J. Neurosci. 19 (2004) 1267–1277. [11] K.R. Leaver, H.N. Allbutt, N.J. Creber, M. Kassiou, J.M. Henderson, Neuroprotective effects of a selective N-methyl-d-aspartate NR2B receptor antagonist in the 6-OHDA rat model of Parkinson’s disease, Clin Exp Pharmacol Physiol. 35 (2008 Nov) 1388–1394. [12] P.A. Loschmann, C. De Groote, L. Smith, U. Wullner, G. Fischer, J.A. Kemp, P. Jenner, T. Klockgether, Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson’s disease, Exp. Neurol. 187 (2004) 86–93. [13] J.E. Nash, P. Ravenscroft, S. McGuire, A.R. Crossman, F.S. Menniti, J.M. Brotchie, The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates l-dopa-

96

L. Truong et al. / Brain Research Bulletin 78 (2009) 91–96

induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of l-dopa in the MPTP-lesioned marmoset model of Parkinson’s disease, Exp. Neurol. 188 (2004) 471–479. [14] G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates, 2nd ed., Academic Press, New York, 1997. [15] M. Sidibe, J.F. Pare, Y. Smith, Nigral and pallidal inputs to functionally segregated thalamostriatal neurons in the centromedian/parafascicular intralaminar nuclear complex in monkey, J. Comp. Neurol. 447 (2002) 286–299. [16] Y. Smith, D.V. Raju, J.F. Pare, M. Sidibe, The thalamostriatal system: a highly specific network of the basal ganglia circuitry, Trends Neurosci. 27 (2004) 520–527.

[17] K. Steece-Collier, L.K. Chambers, S.S. Jaw-Tsai, F.S. Menniti, J.T. Greenamyre, Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunitcontaining N-methyl-d-aspartate receptors, Exp. Neurol. 163 (2000) 239–243. [18] S.T. Warraich, H.N. Allbutt, R. Billing, J. Radford, M. Kassiou, J.M. Henderson, Behavioural effects of a selective NMDA NR1A/2B receptor antagonist in the unilateral 6-OHDA lesioned rat, Brain Res. Bull. 78 (2009) 85–90. [19] R.H. Wessell, S.M. Ahmed, F.S. Menniti, G.L. Dunbar, T.N. Chase, J.D. Oh, NR2B selective NMDA receptor antagonist CP-101,606 prevents levodopa-induced motor response alterations in hemi-parkinsonian rats, Neuropharmacology 47 (2004) 184–194.