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Nelotanserin is a serotonin 2A and 2C (5‐HT2A/2C) inverse agonist that was previously tested in the clinic for rapid‐eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia has however not been investigated. As 5‐HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti‐dyskinetic potential of nelotanserin in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L‐DOPA to induce dyskinesia. On experimental days, they were administered L‐DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L‐DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1 mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1 mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti‐parkinsonian action of L‐DOPA. Our results highlight that nelotanserin may represent an efficacious anti‐dyskinetic drug and provide incremental evidence of the potential benefit of 5‐HT2A/2C antagonism/inverse agonism for drug‐induced dyskinesia in PD. [ABSTRACT FROM AUTHOR]

Rationale: Positive allosteric modulation of metabotropic glutamate type 4 (mGlu4) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). Objectives: We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia. Methods: Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75 mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured. Results: ADX-88178 mildly worsened global PLBs at the dose of 1 mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 212 min (34% increase, P = 0.011), after adding ADX-88178 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses. Conclusions: Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis. [ABSTRACT FROM AUTHOR]

LY-404,039 is an orthosteric agonist of metabotropic glutamate 2 and 3 receptors (mGluR2/3) that may harbour additional agonist effect at dopamine D2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously entered clinical trials as treatment options for schizophrenia. They could therefore be repurposed, if proven efficacious, for other conditions, notably Parkinson's disease (PD). We have previously shown that the mGluR2/3 orthosteric agonist LY-354,740 alleviated 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 marmoset. Unlike LY-404,039, LY-354,740 does not stimulate dopamine D2 receptors, suggesting that LY-404,039 may elicit broader therapeutic effects in PD. Here, we sought to investigate the effect of this possible additional dopamine D2-agonist action of LY-404,039 by assessing its efficacy on dyskinesia, PLBs and parkinsonism in the MPTP-lesioned marmoset. We first determined the pharmacokinetic profile of LY-404,039 in the marmoset, in order to select doses resulting in plasma concentrations known to be well tolerated in the clinic. Marmosets were then injected L-DOPA with either vehicle or LY-404,039 (0.1, 0.3, 1 and 10 mg/kg). The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of global dyskinesia (by 55%, P < 0.01) and PLBs (by 50%, P < 0.05), as well as reduction of global parkinsonism (by 47%, P < 0.05). Our results provide additional support of the efficacy of mGluR2/3 orthosteric stimulation at alleviating dyskinesia, PLBs and parkinsonism. Because LY-404,039 has already been tested in clinical trials, it could be repurposed for indications related to PD. [ABSTRACT FROM AUTHOR]

JNJ-42491293 is a metabotropic glutamate 2 (mGlu2) positive allosteric modulator (PAM) that was radiolabelled with [11C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [11C]-JNJ-42491293 could interact with an unidentified, non-mGlu2 receptor binding site. The brain distribution of [11C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [11C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [11C]-JNJ-42491293 in combination with vehicle or the mGlu2 PAM AZD8529 (0.1, 1 and 10 mg/kg). In the scans in which [11C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10 mg/kg) to [11C]-JNJ-42491293 did not modify the SUVs obtained with [11C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300 µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [11C]-JNJ-42491293 interacts selectively, or even at all, with mGlu2 receptors in the marmoset, in agreement with findings previously reported in macaque and human. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < 0.001), when compared to L-DOPA/vehicle. Similarly, the addition of EMD-281,014 (0.1, 1 and 10 mg/kg) to L-DOPA also significantly decreased the severity of PLBs, by up to 54%, 55% and 53% (each P < 0.001), when compared to L-DOPA/vehicle. Our results suggest that there might be a ceiling to the reduction of dyskinesia and psychosis that can be achieved through antagonism of 5-HT2A receptors. [ABSTRACT FROM AUTHOR]

Activation of metabotropic glutamate 2 (mGlu2) receptors is a potential novel therapeutic approach for the treatment of parkinsonism. Thus, when administered as monotherapy or as adjunct to a low dose of L‐3,4‐dihydroxyphenylalanine (L‐DOPA), the mGlu2 positive allosteric modulator (PAM) LY‐487,379 alleviated parkinsonism in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned primates. Here, we sought to investigate the effect of biphenyl‐indanone A (BINA), a highly selective mGlu2 PAM whose chemical scaffold is unrelated to LY‐487,379, to determine if a structurally different mGlu2 PAM would also confer anti‐parkinsonian benefit. In monotherapy experiments, MPTP‐lesioned marmosets were injected with either vehicle, L‐DOPA/benserazide (15/3.75 mg/kg, positive control) or BINA (0.1, 1, 10 mg/kg). In adjunct to a low L‐DOPA dose experiments, MPTP‐lesioned marmosets were injected with L‐DOPA/benserazide (7.5/1.875 mg/kg) in combination with vehicle or BINA (0.1, 1, 10 mg/kg). Parkinsonism, dyskinesia and psychosis‐like behaviours (PLBs) were then quantified. When administered alone, BINA 1 and 10 mg/kg decreased parkinsonism severity by ~22% (p < 0.01) and ~47% (p < 0.001), when compared with vehicle, which was comparable with the global effect of a high L‐DOPA dose. When administered in combination with a low L‐DOPA dose, BINA 1 and 10 mg/kg decreased global parkinsonism by ~38% (p < 0.001) and ~53% (p < 0.001). BINA 10 mg/kg decreased global dyskinesia by ~94% (p < 0.01) and global PLBs by ~92% (p < 0.01). Our results provide additional evidence that mGlu2 positive allosteric modulation elicits anti‐parkinsonian effects. That this benefit is not related to a particular chemical scaffold suggests that it may be a class effect rather than the effect of a specific molecule. [ABSTRACT FROM AUTHOR]

Nelotanserin is a serotonin 2A and 2C (5-HT 2A/2C ) inverse agonist that was previously tested in the clinic for rapid-eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia has however not been investigated. As 5-HT 2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti-dyskinetic potential of nelotanserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L-DOPA to induce dyskinesia. On experimental days, they were administered L-DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L-DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1 mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1 mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti-parkinsonian action of L-DOPA. Our results highlight that nelotanserin may represent an efficacious anti-dyskinetic drug and provide incremental evidence of the potential benefit of 5-HT 2A/2C antagonism/inverse agonism for drug-induced dyskinesia in PD., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Antagonising the serotonin 2A (5-HT 2A ) 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-HT 2A receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu 2 ) receptors, in which 5-HT 2A blockade and mGlu 2 activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu 2 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-HT 2A antagonism and mGlu 2 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 mGlu 2 positive allosteric modulator LY-487,379 and the 5-HT 2A antagonist EMD-281,014, either alone or in combination, were added to l-DOPA. In the second series of experiments, the mGlu 2/3 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 mGlu 2 blockade would diminish the effects of antagonising 5-HT 2A receptors. To this end, the mGlu 2/3 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 < 0.05) and EMD-281,014 (by 38%, P < 0.01). The anti-dyskinetic and anti-psychotic effects of the combination LY-354,740/EMD-281,014 were also greater than the ones conferred by LY-354,740 (by 57% for dyskinesia and 54% for PLBs, both P < 0.001) and EMD-281,014 (by 61% for dyskinesia and 53% for PLBs, both P < 0.001). The anti-parkinsonian action of 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 mGlu 2 activation may enhance the anti-dyskinetic and anti-psychotic effects of 5-HT 2A blockade and could provide relief to PD patients with dyskinesia and psychotic symptoms beyond what can be achieved with current therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 3 ) 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 < 0.0001) and decreased duration of on-time with disabling dyskinesia by 88% (P = 0.0491). Ondansetron 0.1 mg/kg reduced the severity of global PLBs by 80% (P < 0.0001) and suppressed on-time with disabling PLBs (P = 0.0213). Ondansetron enhanced the anti-parkinsonian action of l-DOPA, reducing global parkinsonism by 53% compared to l-DOPA (P = 0.0004). These results suggest that selective blockade of the 5-HT 3 receptor with ondansetron may be an effective approach to alleviate l-DOPA-related complications., (Copyright © 2020. Published by Elsevier Ltd.)