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The common marmoset has emerged as a popular model in neuroscience research, in part due to its reproductive efficiency, genetic and neuroanatomical similarities to humans and the successful generation of transgenic lines. Stereotaxic procedures in marmosets are guided by 2D stereotaxic atlases, which are constructed with a limited number of animals and fail to account for inter-individual variability in skull and brain size. Here, we developed a frameless imaging-guided stereotaxic system that improves upon traditional approaches by using subject-specific registration of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) data to identify a surgical target, namely the putamen, in two marmosets. The skull surface was laser-scanned with to create a point cloud that was registered to the 3D reconstruction of the skull from CT. Reconstruction of the skull, as well as of the brain from MR images, was crucial for surgical planning. Localisation and injection into the putamen was done using a 6-axis robotic arm controlled by a surgical navigation software (BrainsightTM). Integration of subject-specific registration and frameless stereotaxic navigation allowed target localisation specific to each animal. Injection of alpha-synuclein fibrils into the putamen triggered progressive neurodegeneration of the nigro-striatal system, a key feature of Parkinson’s disease. Four months post-surgery, a PET scan found evidence of nigro-striatal denervation, supporting accurate targeting of the putamen during co-registration and subsequent surgery. Our results suggest that this approach, coupled with frameless stereotaxic neuronavigation, is accurate in localising surgical targets and can be used to assess endpoints for longitudinal studies.

The article contains a brief retrospective assessment of the reasons given by various scholars and observers for the breakdown of the Soviet Union under Mikhail Gorbachev’s leadership and it situates that crisis in the larger context of history and the imperial legacy of the Russian state. It particularly looks at the issue of nationality as an ethnic, cultural and linguistic concept vis-a-vis the universalistic notion of empire as a community of destiny among diverse people. The author compares the Soviet Union’s structure as a ‘non classical’ empire to those of other European states and especially to Germany’s which has also evolved from being a loose Central and East European ‘Reich’ inspired by the Roman and Carolingian heritage – to becoming a federal nation surrounded by smaller countries that share with it ancient civilisational and political legacy. Whereas Germany is gradually asserting leadership among many of its former dependencies and in the post-Brexit European Union as a whole, Russia is led by geographical and strategic compulsions to rebuild a Eurasian confederal association with erstwhile Soviet Republics and possessions of the Tsarist Empire, in conformity with its location between the ‘West’, the Islamosphere and the Chinese world. Will Russia be able to create a synthesis between the Slav Orthodox Oikoumene envisioned by Nikolay Danilevsky and the Eurasian syncretistic model promoted by Lev Gumilyov?

PURPOSE Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.

In previous experiments, we have discovered that positive allosteric modulation of metabotropic glutamate 2 (mGlu

Parkinson’s disease (PD) psychosis afflicts over half of patients and poses a significant burden on quality of life. The aetiology of PD psychosis is multifactorial and likely arises from the complex interaction between dopamine replacement therapy and disease state. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset is a validated model to predict the efficacy of therapeutic compounds for treatment-related complications, including PD psychosis. In this model, psychosis-like behaviours (PLBs) encompass stereotypies that are idiosyncratic in nature and reproducible with each L-3,4-dihydroxyphenylanaline (L-DOPA) administration. In the present study, we sought to expand upon the existing repertoire of PLBs through the characterisation of novel stereotypical behaviours that appear dependent on the environment. We then discuss our findings in the context of clinical reports on stereotypical behaviours termed “punding” in subjects with PD, which consists of stereotypical repetitive and senseless behaviours. The poor understanding of the pathophysiology governing punding and consequent lack of effective therapies stand to benefit from enhanced characterisation of these stereotypical behaviours in a validated pre-clinical model. We hope that further characterisation of PLBs in the MPTP-lesioned marmoset will be helpful in the evaluation of interventions that seek to alleviate PD psychosis symptoms.

Advanced Parkinson’s disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu2) receptors with the prototypical positive allosteric modulator (PAM) LY-487,379 is efficacious at alleviating both dyskinesia and psychosis-like behaviours (PLBs), while simultaneously enhancing the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we assessed the effects of CBiPES, a mGlu2 PAM derived from LY-487,379, but with improved pharmacokinetic properties. Six MPTP-lesioned marmosets with reproducible dyskinesia and PLBs were administered L-DOPA in combination with vehicle or CBiPES (0.1, 1 and 10 mg/kg), after which their behaviour was rated. CBiPES 10 mg/kg reduced global dyskinesia by 60% (P

Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson’s disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (− 36% with 0.1 mg/kg, P

Monoamine oxidase (MAO) type B (MAO-B) inhibition was shown to confer anti-parkinsonian benefit as monotherapy and adjunct to l-3,4-dihydroxyphenylalanine (l-DOPA) in clinical trials. Here, we explore the anti-parkinsonian effect of MAO type A (MAO-A) inhibition as monotherapy, as the enzyme MAO-A is also encountered within the primate and human basal ganglia, where it metabolises dopamine, albeit to a lesser extent than MAO-B. In six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, we assessed the anti-parkinsonian effect of the reversible MAO-A inhibitor moclobemide (0.1 and 1 mg/kg) as monotherapy and compared it to that of l-DOPA and vehicle treatments. Moclobemide significantly reversed parkinsonism (by 39%, P

We have recently shown that activation of metabotropic glutamate 2 (mGlu2) receptors through positive allosteric modulation and orthosteric stimulation is a novel approach to reduce L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia and dopaminergic psychosis in Parkinson’s disease (PD). We have obtained these benefits with the mGlu2-positive allosteric modulator (PAM) LY-487,379 and the mGlu2/3 orthosteric agonist (OA) LY-354,740 in experiments conducted in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to pharmacologically characterise the anti-dyskinetic and anti-psychotic effects of LY-487,379 and LY-354,740, by assessing whether their benefits would be reversed by the mGlu2/3 orthosteric antagonist LY-341,495. Six MPTP-lesioned marmosets exhibiting stable dyskinesia and psychosis-like behaviours (PLBs) entered the experiments. In the first series of experiments, animals were injected l-DOPA in combination with either vehicle, LY-487,379 (10 mg/kg), LY-341,495 (1 mg/kg) or LY-487,379/LY-341,495. In the second series of experiments, marmosets were injected l-DOPA in combination with either vehicle, LY-354,740 (1 mg/kg), LY-341,495 (1 mg/kg) or LY-354,740/LY-341495. As we previously demonstrated, both LY-487,379 and LY-354,740 alleviated dyskinesia (by 44% and 47%, both P

In recent studies performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD), we have demonstrated that activation of the metabotropic glutamate 2 (mGlu2) receptor with the orthosteric agonist (OA) LY-354,740 and the positive allosteric modulator (PAM) LY-487,379 is effective at alleviating both dyskinesia and psychosis-like behaviours (PLBs) triggered by the administration of l-3,4-dihydroxyphenylalanine (l-DOPA). Because mGlu2 OAs and PAMs bind to different sites on the receptor, we hypothesised that greater reductions of dyskinesia and PLBs would be obtained upon concurrent administration of LY-354,740 and LY-487,379. In experiments performed in six MPTP-lesioned marmosets, we administered LY-354,740 (0.1 mg/kg), LY-487,379 (1 mg/kg), LY-354,740 (0.1 mg/kg) + LY-487,379 (1 mg/kg), or vehicle, in combination with l-DOPA and determined the effect of each treatment on dyskinesia, PLBs, and parkinsonism. When compared to vehicle, LY-354,740 and LY-487,379, administered alone or concurrently, significantly reduced dyskinesia. The combination LY-354,740 + LY-487,379 provided mild additional benefit when compared to LY-487,379 alone, but not compared to LY-354,740. For PLBs, when compared to vehicle treatment, LY-354,740, LY-487,379, and combination thereof all alleviated the abnormal behaviours, but the combination LY-354,740 + LY-487,379 did not provide greater relief than either drug alone. The anti-parkinsonian effect of l-DOPA was not altered by any of the treatments. Our results provide further evidence that mGlu2 activation might be a novel approach to treat l-DOPA-induced dyskinesia and dopaminergic psychosis in PD. However, they do not suggest that greater therapeutic effect would be achieved upon combining an mGlu2 OA and an mGlu2 PAM.

Antagonising the serotonin 2A (5-HT

Advanced Parkinson's disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu

Parkinson's disease (PD) psychosis afflicts over half of patients and poses a significant burden on quality of life. The aetiology of PD psychosis is multifactorial and likely arises from the complex interaction between dopamine replacement therapy and disease state. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset is a validated model to predict the efficacy of therapeutic compounds for treatment-related complications, including PD psychosis. In this model, psychosis-like behaviours (PLBs) encompass stereotypies that are idiosyncratic in nature and reproducible with each L-3,4-dihydroxyphenylanaline (L-DOPA) administration. In the present study, we sought to expand upon the existing repertoire of PLBs through the characterisation of novel stereotypical behaviours that appear dependent on the environment. We then discuss our findings in the context of clinical reports on stereotypical behaviours termed "punding" in subjects with PD, which consists of stereotypical repetitive and senseless behaviours. The poor understanding of the pathophysiology governing punding and consequent lack of effective therapies stand to benefit from enhanced characterisation of these stereotypical behaviours in a validated pre-clinical model. We hope that further characterisation of PLBs in the MPTP-lesioned marmoset will be helpful in the evaluation of interventions that seek to alleviate PD psychosis symptoms.

In Parkinson's disease (PD), management of L-3,4-dihydroxyphenylalanine (l-DOPA)-related complications, such as l-DOPA induced dyskinesia and psychosis, remains inadequate, which poses a significant burden on the quality of life of patients. We have shown, in the hemi-parkinsonian rat model of PD, that the selective serotonin type 3 (5-HT

In recent studies performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease (PD), we have demonstrated that activation of the metabotropic glutamate 2 (mGlu

Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1 mg/kg, P 0.05; - 38% with 1 mg/kg, P 0.01; - 47% with 10 mg/kg, P 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.

Virtually every patient affected by Parkinson’s disease (PD) eventually requires treatment with l-3,4-dihydroxyphenylalanine (l-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT2A) receptors appears to be an effective way to reduce both dyskinesia and psychosis, whether it has the potential to eliminate the two phenomena remains to be determined. In a previous study, we showed that highly selective 5-HT2A receptor blockade with EMD-281,014, at plasma levels comparable to those achieved in the clinic, reduced dyskinesia and psychosis-like behaviours (PLBs), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine whether further increasing the dose would result in greater therapeutic benefit or if maximal effectiveness was achieved at lower doses. Six MPTP-lesioned marmosets with stable dyskinesia and PLBs were administered EMD-281,014 (0.1, 1 and 10 mg/kg) or vehicle in combination with l-DOPA and the effect on dyskinesia, PLBs and parkinsonism was assessed. Administration of EMD-281,014 (0.1, 1 and 10 mg/kg) in combination with l-DOPA resulted in a significant reduction in the severity of dyskinesia, by up to 63%, 64% and 61% (each P

Blockade of serotonin 2A (5-HT2A) receptors is regarded as an anti-dyskinetic and anti-psychotic strategy in Parkinson's disease (PD). However, the 5-HT2A antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD-281,014 is the most selective 5-HT2A antagonist available, with approximately 2,000-fold selectivity over serotonin 2C (5-HT2C) receptors. EMD-281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD-281,014 on dyskinesia and psychosis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. We first determined the pharmacokinetic profile of EMD-281,014 in the marmoset, after which doses leading to clinically-relevant plasma levels (0.01, 0.03 and 0.1 mg/kg) or vehicle were administered to MPTP-lesioned marmosets, in combination with L-3,4-dihydroxyphenylalanine ( l -DOPA). The effects of EMD-281,014 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were then evaluated. When added to l -DOPA, EMD-281,014 (0.03 and 0.1 mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P l -DOPA/vehicle. EMD-281,014 (0.03 and 0.1 mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P l -DOPA anti-parkinsonian action. Our results suggest that highly-selective 5-HT2A receptor blockade with EMD-281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability.

Nefazodone is an anti-depressant that interacts with a wealth of pharmacological targets, including some that may exert anti-dyskinetic and anti-psychotic effects in Parkinson’s disease (PD), notably serotonin 1A and 2A receptors. In this study, we sought to determine the effect of nefazodone on l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Six common marmosets developed parkinsonism following administration of MPTP, after which they were treated chronically with l-DOPA to induce stable dyskinesia and PLBs. In behavioural experiments, nefazodone (0.01, 0.1 and 1 mg/kg) or vehicle was administered in combination with l-DOPA and its effects on dyskinesia, PLBs and parkinsonian disability were assessed. The addition of nefazodone 0.01, 0.1 and 1 mg/kg to l-DOPA reduced the severity of peak dose dyskinesia by ≈ 21%, ≈ 39% and ≈ 42% (all P

Background Parkinson's disease (PD) psychosis is a distressing condition that affects up to 60% of patients at the advanced stages of the disease. It significantly impairs patients' and caregivers' quality of life. Current therapeutic options are limited, with only 2 drugs, clozapine and pimavanserin, demonstrating efficacy in randomised controlled trials. These 2 drugs harbour significant affinity for serotonin 2A (5-HT2A) receptors, at which they act as antagonists. Mianserin is a non-selective, clinically-available, anti-depressant that blocks 5-HT2A receptors. Here, we hypothesised that mianserin would effectively alleviate PD psychosis. Methods We tested the anti-psychotic potential of mianserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six MPTP-lesioned marmosets exhibiting psychosis-like behaviours (PLBs) were administered l -3,4-dihydroxyphenylalanine ( l -DOPA) in combination with mianserin (0.3, 1 and 3 mg/kg) or vehicle, after which the severity of PLBs was rated. We also assessed the effect of mianserin on l -DOPA-induced dyskinesia and parkinsonian disability. Results The addition of mianserin 3 mg/kg to l -DOPA led to a 23% reduction of PLBs (P l -DOPA/vehicle. Dyskinesia was reduced, by ≈ 41% (P l -DOPA, compared to l -DOPA/vehicle. However, mianserin 3 mg/kg reduced duration of l -DOPA anti-parkinsonian action, by ≈ 18% (P l -DOPA/vehicle. Conclusions Our results suggest that mianserin, a clinically-available anti-depressant, may be effective to alleviate both PD psychosis and dyskinesia, but may hinder l -DOPA anti-parkinsonian action, which limits its potential clinical usefulness.

Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N-methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT1) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated. In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P Our results suggest that GlyT1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action.

The use of oocytes recovered from prepubertal donors for in vitro embryo production has great potential for accelerating the rate of genetic gain in the dairy industry. However, these oocytes are known to be less developmentally competent than those from adult donors. In this study, we investigated the effect of age and gonadotropin stimulation in Holstein heifers subjected to oocyte collection every two weeks between 2 and 6 months of age. In order to assess the effect of gonadotropin stimulation, animals were subjected to one of three treatments, namely Short (ST; 36-42 h), Long (LT; ≥72 h) and No Treatment (NT) prior to laparoscopic ovum pick-up (LOPU). Our results show that the LT significantly improved the proportion of large follicles (5 mm diameter) present in the ovary (LT 34.0% vs. ST 11.2% vs. NT 2.4%, P 0.05), as well as the percentage of good-quality cumulus oocyte complexes (COCs) recovered (LT 95.3 ± 18% vs. ST 85.4 ± 22% vs. NT 82.2 ± 14%, P 0.05) and blastocyst rate (LT 36.7 ± 26% vs. ST 18.3 ± 15% vs. NT 16.7 ± 9%, P 0.05). Recovery rate was affected by treatment (LT 70.4 ± 25 vs. ST 85.4 ± 29 vs. NT 72.7 ± 23, P 0.05). To assess the impact of age, data was grouped into100 days (A), 100-130 days (B) and130 days (C) of age at LOPU. We found that as animals got older, although the average number of COCs per donor per LOPU declined (A: 17.5 ± 11 vs. B: 14.7 ± 7 vs. C: 11.9 ± 8), the blastocyst rate increased (A: 12.8 ± 20% vs. B: 17.1 ± 21% vs. C: 21.8 ± 25%, P 0.05). We also evaluated the incidence of polyspermy and confirmed it is a critical limitation for IVF in calf oocytes. The incidence of polyspermy was unaffected by gonadotropin treatment, but significantly decreased with age. The capacity for full development to term of in vitro produced embryos from calf oocytes was tested by embryo transfer into 21 synchronized adult recipients, which resulted in 13 pregnancies (62%), full development to term and healthy calves born. Finally, the study allowed evaluating the safety of the procedure since, on average, each animal was subjected to 8 LOPU procedures over a period of 4 months. Our results showed that the procedure is safe (no incidents during laparoscopy), and was not harmful for the reproductive future of the animals, as those that were bred became pregnant after reaching sexual maturity.

Psychosis and dyskinesia significantly diminish the quality of life of patients with advanced Parkinson's disease (PD). Available treatment options are unfortunately few and their use is limited by adverse effects. We have recently shown that activation of metabotropic glutamate 2 and 3 (mGlu2/3) receptors produced significant relief of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in experimental models of PD. Here, using the highly-selective mGlu2 positive allosteric modulator (PAM) LY-487,379, we seek to determine the contribution of selective mGlu2 activation on both L-DOPA-induced PLBs and dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We first determined the pharmacokinetic (PK) profile of LY-487,379 in the common marmoset, following which we administered it (0.1, 1 and 10 mg/kg) or its vehicle to 6 MPTP-lesioned marmosets previously exposed to L-DOPA to elicit stable PLBs and dyskinesia. We found that LY-487,379 provided a ≈45% reduction of the global PLBs observed and reduced global dyskinesia score by ≈ 55%. Moreover, LY-487,379 enhanced the anti-parkinsonian effect of L-DOPA, by reducing global parkinsonian score by ≈ 15%. Our data suggest that selective mGlu2 positive allosteric modulation with LY-487,379 may represent a potential therapeutic approach to alleviate both L-DOPA-induced PLBs and dyskinesia in PD.

Selective blockade of serotonin 2A (5-HT

Antagonising the serotonin 2A (5-HT2A) receptor is an efficacious way to alleviate dyskinesia and psychosis in Parkinson's disease (PD). However, previous research indicates that there might be a limit to the effects conferred by this approach. 5-HT2A receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu2) receptors, in which 5-HT2A blockade and mGlu2 activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu2 activation reduces both dyskinesia and psychosis-like behaviours (PLBs) induced by L-3,4-dihydroxyphenylalanine ( l -DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we hypothesised that concurrent 5-HT2A antagonism and mGlu2 activation would provide greater anti-dyskinetic and anti-psychotic benefits than either approach alone. We conducted 3 series of experiments in the MPTP-lesioned marmoset. In the first series of experiments, the mGlu2 positive allosteric modulator LY-487,379 and the 5-HT2A antagonist EMD-281,014, either alone or in combination, were added to l -DOPA. In the second series of experiments, the mGlu2/3 orthosteric agonist LY-354,740 and EMD-281,014, either alone or in combination, were added to l -DOPA. In the last series of experiments, we investigated whether mGlu2 blockade would diminish the effects of antagonising 5-HT2A receptors. To this end, the mGlu2/3 orthosteric antagonist LY-341,495 and EMD-281,014, either alone or in combination, were added to l -DOPA. We found that the anti-dyskinetic effect of the combination LY-487,379/EMD-281,014 was greater than the ones conferred by LY-487,379 (by 35%, P l -DOPA was maintained with all treatments. Lastly, the addition of LY-341,495 abolished the therapeutic effects of EMD-281,014 on dyskinesia and PLBs. Our results suggest that mGlu2 activation may enhance the anti-dyskinetic and anti-psychotic effects of 5-HT2A blockade and could provide relief to PD patients with dyskinesia and psychotic symptoms beyond what can be achieved with current therapies.

Parkinson’s disease (PD) psychosis is encountered in as many as 50% of patients with advanced disease. Treatment options for PD psychosis are few. In fact, only clozapine and pimavanserin have shown efficacy in randomised controlled trials. Clinicians are often reluctant to prescribe the former, due to the risk of agranulocytosis, while the latter is not widely available yet. Because it is already clinically available and exhibits high affinity for serotonin 2A receptors, a target with which both clozapine and pimavanserin interact, we hypothesised that the anti-depressant mirtazapine might be effective to alleviate PD psychosis. Here, we tested the anti-psychotic potential of mirtazapine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Five MPTP-lesioned marmosets exhibiting psychosis-like behaviours were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with mirtazapine (0.1, 1 and 10 mg/kg) or vehicle. We also tested the effect of mirtazapine on L-DOPA-induced dyskinesia. The addition of mirtazapine 10 mg/kg to L-DOPA reduced psychosis-like behaviours by 50% (P < 0.05) and dyskinesia by 29% (P < 0.01), when compared to L-DOPA/vehicle. Importantly, the antipsychotic and antidyskinetic effects of mirtazapine were achieved without hindering L-DOPA anti-parkinsonian action. Our results suggest that mirtazapine may be effective to alleviate PD psychosis and, because the drug is clinically available, clinical trials that would assess its anti-psychotic efficacy in PD could be rapidly undertaken, hopefully leading to a new treatment option for this debilitating condition.

While the cage refinement is a necessary step towards improving the welfare of research rats, increasing the complexity and surface area of the living space of an animal may have physiological impacts that need to be taken into consideration. In this study, ketamine (80 mg/kg) and xylazine (10 mg/kg) caused a short duration anesthesia that was significantly decreased in Sprague-Dawley rats housed in multilevel cages (MLC), compared to rats housed in standard cages (SDC). The withdrawal reflex, the palpebral reflexes and the time-to-sternal all occurred earlier in MLC housed rats, suggesting an effect of housing on the physiology of the rats. In addition, during anesthesia, cardiac frequencies were increased in animals housed in the smaller SDC. Respiratory frequencies, the blood oxygen saturation and rectal temperatures during anesthesia did not vary between conditions during the anesthesia. While xylazine pharmacokinetics were unchanged with caging conditions, the clearance and half-lives of ketamine and its metabolite, norketamine, were altered in the rats housed in MLC. Finally, while no difference was ultimately seen in rat body weights, isolated liver and adrenal gland weights were significantly lighter in rats housed in the MLC. Increasing cage sizes, while having a positive impact on wellbeing in rats, can alter anesthetic drug metabolism and thus modify anesthesia parameters and associated physiological processes.

In Parkinson's disease (PD), management of L-3,4-dihydroxyphenylalanine ( l -DOPA)-related complications, such as l -DOPA induced dyskinesia and psychosis, remains inadequate, which poses a significant burden on the quality of life of patients. We have shown, in the hemi-parkinsonian rat model of PD, that the selective serotonin type 3 (5-HT3) receptor antagonists ondansetron and granisetron decreased the severity of established dyskinesia, and ondansetron even attenuated the development of dyskinesia. Here, we seek to confirm these favourable data on dyskinesia and to explore the effect of ondansetron on the severity of psychosis-like behaviours (PLBs) in the gold standard model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate. We first determined the pharmacokinetic profile of ondansetron in the marmoset. Subsequently, six MPTP-lesioned marmosets were administered l -DOPA chronically until they exhibited stable and reproducible dyskinesia and PLBs upon each administration of l -DOPA. On behavioural assessment days, ondansetron (0.01, 0.1 and 1 mg/kg) or vehicle was administered in conjunction with l -DOPA, and the severity of dyskinesia, PLBs and parkinsonism was evaluated. Ondansetron 0.1 mg/kg alleviated global dyskinesia severity by 73% (P l -DOPA, reducing global parkinsonism by 53% compared to l -DOPA (P = 0.0004). These results suggest that selective blockade of the 5-HT3 receptor with ondansetron may be an effective approach to alleviate l -DOPA-related complications.

This paper describes the test plan and the main results achieved by UMS during a space evaluation of its second generation 0.5 μm GaN RF power bar technology, called GH50-20. The space evaluation tests results are summarised: a life time higher than 5.106 h @ 200 °C is found, SEE, TID and DD radiation hardness safe area were defined, and failure rate below 10 FIT @ 200 °C was determined. The results also include demonstration of representative integrated circuits up to 130 W RF power level when operated in L-band in continuous wave (CW) mode. The GH50-20 technology has successfully passed the space evaluation program and is deemed suitable for use in space.

Bitopertin is a potent glycine transporter 1 (GlyT1) inhibitor that has undergone clinical trials for diverse disorders and has a well-documented pharmacokinetic (PK) profile in humans. Even though pre-clinical studies have demonstrated potential therapeutic effects on cognition and neuropathic pain, the PK profile of bitopertin in the rat has been partly disclosed and no study reporting its PK profile in the common marmoset has been published. The aim of this study was to develop and validate a sensitive and selective high-performance liquid chromatography coupled with heat assisted electrospray ionisation tandem mass spectrometry (HPLC-HESI-MS/MS) assay to quantify bitopertin in the rat (Sprague-Dawley) and the common marmoset (Callithrix jacchus) plasma after administration of 1.0 mg/kg subcutaneously. The analytical method consisted of protein precipitation followed by HPLC-HESI–MS/MS. Chromatographic separation was carried out on a Thermo Scientific Aquasil C18 analytical column (100 x 2.1 mm I.D., 5.0 μm) kept at 50°C using acetonitrile and water both fortified at 0.1% (v/v) with formic acid at a ratio 55:45 as mobile phase with a constant flow rate of 250 μL/min. The calibration function was linear in the range of 0.3-200.0 ng/mL in rat plasma. The intra-day and inter-day precision and accuracy were within ± 15% at all concentrations. The limit of detection (LOD) and quantitation (LOQ) in rat plasma were 0.08 and 0.3 ng/mL, respectively. This method has demonstrated high sensitivity and specificity and was successfully applied to measure bitopertin in rat and marmoset plasma, allowing the investigation of its PK properties in both species.

Virtually every patient affected by Parkinson's disease (PD) eventually requires treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT

Oocytes collected from prepubertal animals are known to be less developmentally competent than those from adult animals. There is evidence suggesting that acquisition of developmental competence in bovine oocytes may be linked to the expression profile of genes in the granulosa cells (GCs). Cumulus-oocyte complexes (COC) and GCs were collected from 12 Holstein heifers between 2 and 6 months of age (nine follicle-stimulating hormone [FSH] treated and three untreated) and eight FSH-treated cows. The COCs from prepubertal animals were matured, fertilized, and cultured in vitro to assess development to the blastocyst stage. The relative messenger RNA (mRNA) abundance of FSHR, StAR, CYP19A1, HSD3B1, CX43, FOXO1, and XIAP in GCs were quantified by real-time quantitative polymerase chain reaction. Results from this study revealed that GCs of prepubertal animals respond to FSH treatment by increasing mRNA levels of genes promoting estradiol synthesis and follicular growth ( FSHR and CYP19A1), and preventing cell apoptosis ( XIAP), and by decreasing mRNA levels of genes promoting progesterone production ( StAR and HSD3B1). This study also revealed that the relative mRNA abundance of FOXO1 in GCs is associated with oocyte competence to support embryo development to the blastocyst stage in prepubertal Holstein heifers.

Blockade of serotonin 2A (5-HT

Drugs modulating the metabotropic glutamate type 2 receptor (mGluR2) activity may have therapeutic benefits in treating a large spectrum of neuro-psychiatric disorders, from schizophrenia to Parkinson's disease, both as a symptomatic therapy and potential disease-modifying paradigm. LY-487,379 is a highly selective mGluR2 positive allosteric modulator that is widely used to study mGluR2 function using experimental animal models. The common marmoset is a small primate that has long been used in neuroscience. However, given its small size and small circulating blood volume, conducting studies to determine the PK profile of LY-487,379 is challenging. We developed and validated a sensitive and selective analytical method that enables quantification of LY-487,379 using a limited volume of plasma (10 μL). The analytical method consists of protein precipitation followed by high-performance liquid chromatography with heat assisted electrospray ionization mass spectrometry (HPLC-HESI-MS/MS). The chromatographic separation was achieved using gradient elution with a mobile phase consisting of acetonitrile and 0.01% formic acid in water on a Thermo Scientific Aquasil C18 analytical column (100 × 2.1 mm I.D., 5 μm) operating at 40 °C and at a flow rate of 300 μL/min. The method displays a linear relationship ranging from 0.2 to 100 ng/mL. Intra- and inter-day relative standard deviations are

The goal of the present work was to compare cloud point extraction and extraction using ionic liquid for the separation of furfural from a dilute aqueous solution. Aqueous solutions of the biodegradable non-ionic surfactant Dehydol LT 7 (equivalent to C15E7) and the pure ionic liquid (IL) 1-butyl-3-methylimidazolium hexafluorophosphate ([C4C1im]PF6) were investigated as extraction solvents. Phase diagrams of binary (water/surfactant) and pseudo-binary (water/surfactant/solute) systems were plotted. The extraction results were expressed by the following responses: percentage of solute extracted, E (%), residual concentrations of solute and surfactant in aqueous phase (Xs,w and Xt,w, respectively), and volume fraction of coacervate at equilibrium (ϕC). For each parameter, the experimental results were fitted to empirical equations in three dimensions. The aim of this study was to find the best compromise between E and the other parameters (Xs,w, Xt,w, and ϕC, as low as possible). The comparison betw...

Trazodone is a clinically available anti-depressant that exhibits affinity for serotonin 1A and 2A receptors, as well as for alpha-adrenoceptors, suggesting that it may be useful to treat l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia and psychosis that are encountered in advanced Parkinson’s disease (PD). Here, we investigated the anti-dyskinetic and anti-psychotic effects of trazodone in the parkinsonian non-human primate. 6 common marmosets were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following repeated administration of l-DOPA to induce stable dyskinesia and psychosis-like behaviours (PLBs), trazodone (0.1, 1 and 10 mg/kg) or vehicle was administered in combination with l-DOPA and its effects on dyskinesia, PLBs and parkinsonism were determined. The addition of trazodone 10 mg/kg to l-DOPA reduced peak dose dyskinesia by ≈ 39% (P

International audience; S28463 (S28), a ligand for Toll-like receptor 7/8, has been shown to have antiinflammatory properties in rodent models of allergic asthma. The principle goal of this study was to assess whether these antiinflammatory effects can also be observed in a nonhuman primate (NHP) model of allergic asthma. NHPs were sensitized then challenged with natural allergen, Ascaris suum extract. The animals were treated with S28 orally before each allergen challenge. The protective effect of S28 in NHPs was assessed by measuring various asthma-related phenotypes. We also characterized the metabolomic and proteomic signatures of the lung environment and plasma to identify markers associated with the disease and treatment. Our data demonstrate that clinically relevant parameters, such as wheal and flare response, blood IgE levels, recruitment of white blood cells to the bronchoalveolar space, and lung responsiveness, are decreased in the S28-treated allergic NHPs compared with nontreated allergic NHPs. Furthermore, we also identified markers that can distinguish allergic from nonallergic or allergic and drug-treated NHPs, such as metabolites, phosphocreatine and glutathione, in the plasma and BAL fluid, respectively; and inflammatory cytokines, IL-5 and IL-13, in the bronchoalveolar lavage fluid. Our preclinical study demonstrates that S28 has potential as a treatment for allergic asthma in primate species closely related to humans. Combined with our previous findings, we demonstrate that S28 is effective in different models of asthma and in different species, and has the antiinflammatory properties clinically relevant for the treatment of allergic asthma.

Selective blockade of serotonin 2A (5-HT2A) receptors is a promising strategy to reduce L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia and has shown efficacy in a Phase III clinical trial for dopaminergic psychosis in Parkinson's disease (PD). However, pre-clinical and clinical evidence suggest that, while this approach may be effective and well tolerated, there might be a ceiling beyond which no further therapeutic benefit might be achieved. There is mounting evidence that 5-HT2A receptors form a functional hetero-complex with metabotropic glutamate 2 (mGlu2) receptors, with antagonism of 5-HT2A receptors and activation of mGlu2 receptors producing similar effects on the Gi/Gq signalling ratio at the intra-cellular level. Based on this interaction between 5-HT2A and mGlu2 receptors, we hypothesised that activation of mGlu2 receptors would alleviate dyskinesia and psychosis in PD. LY-354,740 is a selective mGlu2/3 orthosteric agonist that was previously tested in the clinic. In experiments conducted in the 6-hydroxydopamine (6-OHDA)-lesioned rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset, we found that mGlu2/3 activation with LY-354,740 significantly reduced the expression of dyskinesia and psychosis-like behaviours, while simultaneously enhancing l-DOPA therapeutic benefit. Moreover, mGlu2/3 activation with LY-354,740 attenuated the development of dyskinesia. These data indicate that activation of mGlu2/3 receptors is a therapeutic strategy that may provide relief for both motor and-non-motor treatment-related complications in PD.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neuro-toxin that has been employed to model Parkinson’s disease in non-human primates for over 3 decades. Despite its use for such a long period, little is known about the effects of MPTP on reproductive function. Here, we report the case of a male marmoset which was able to procreate 1.5 year after having been administered the toxin. We also report on 1 male and 1 female MPTP-lesioned marmosets which produced babies after being housed together for 5 years. These cases suggest that MPTP may not interfere with marmoset reproductive function or that if it does, it may be for a limited period of time.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neuro-toxin that has been employed to model Parkinson’s disease in non-human primates for over 3 decades. Despite its use for such a long period, little is known about the effects of MPTP on reproductive function. Here, we report the case of a male marmoset which was able to procreate 1.5 year after having been administered the toxin. We also report on 1 male and 1 female MPTP-lesioned marmosets which produced babies after being housed together for 5 years. These cases suggests that MPTP may not interfere with marmoset reproductive function or that if it does, it may be for a limited period of time.

UMS have fully qualified the first AlGAN/GaN on SiC HFET technology in Europe for high RF power applications up to C band. Reliability results presented in this paper demonstrate GH50-10 technology reached a high level of maturity. The qualification procedure includes environmental test, end of life characterisation, definition of the DC and RF Safe Operating Area and a preliminary evaluation of the failure rate. From storage test, a failure mechanism related to the increase of the gate leakage current has been characterised with an activation energy of 2.1 eV. While the manufacturing process has been optimised to prevent the inverse piezoelectric effect, a runaway phenomenon of the drain current was identified to be the wear out mechanism. The activation energy of 1.82 eV leads to a T 50 above 3 × 10 7 h at 175 °C. Robustness test up to a VSWR of |10| were performed. A failure rate of 57 FIT is extracted at 175 °C from more than 200 000 cumulated component hours over 70 devices.

We present a new low-frequency noise model of a GaInP-GaAs HBT and the associated extraction process from measurements. Specific measurements enable us to locate the two dominant low-frequency noise sources. Their spectral densities extraction as a function of the emitter bias current is then performed and a normalized scalable model is deduced. The cyclostationarity of the low-frequency noise sources is justified. The whole noise model including the shot noise source is implemented in the nonlinear HBT model used in the United Monolithic Semiconductors foundry. In order to verify the validity of the scalable noise model, several voltage-controlled oscillators with different center frequencies and tuning bandwidth have been designed and processed. Comparisons between the predicted performances and experimental results show an excellent agreement and validate the proposed low-frequency noise modeling of multifinger HBTs.

ACL; International audience