Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P  < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P  < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.

Autoradiographic labelling of metabotropic glutamate type 2/3 receptors in the hemi-parkinsonian rat brain.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the treatment of choice for Parkinson's disease (PD) motor symptoms, but its chronic use is hindered by complications such as dyskinesia. Pre-clinical studies discovered that activation of metabotropic glutamate type 2 and 3 (mGlu2/3) receptors alleviates L-DOPA-induced dyskinesia. To gain mechanistic insight into the anti-dyskinetic activity of mGlu2/3 activation, we performed autoradiographic binding with [3H]-LY-341,495 in brain sections from L-DOPA-treated 6-hydroxydopamine (6-OHDA)-lesioned rats that developed mild or severe dyskinesia, as well as L-DOPA-untreated 6-OHDA-lesioned and sham-lesioned animals. In the ipsilateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats showed a decrease in [3H]-LY-341,495 binding in the entopeduncular nucleus (EPN, 30 % vs sham-lesioned rats, P<0.05), globus pallidus (GP, 28 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (49 % vs sham-lesioned rats, P<0.05; 45 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001). Severely dyskinetic 6-OHDA-lesioned rats exhibited an increase in binding in the primary motor cortex (43 % vs mildly dyskinetic 6-OHDA-lesioned rats, P<0.05). In the contralateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats harboured a decrease in binding in the EPN (30 % vs sham-lesioned rats; 24 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05), GP (34 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (50 % vs sham-lesioned rats; 44 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Severely dyskinetic 6-OHDA-lesioned rats presented a decrease in binding in the GP (30 % vs sham-lesioned rats; 19 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Abnormal involuntary movements scores of 6-OHDA-lesioned animals were positively correlated with [3H]-LY-341,495 binding in the ipsilateral striatum, ipsilateral EPN, ipsilateral primary motor cortex and contralateral primary motor cortex (all P<0.05). These results suggest that alterations in mGlu2/3 receptor levels may be part of an endogenous compensatory mechanism to alleviate dyskinesia.

[3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.

Anticonvulsant Agents for Treatment of Restless Legs Syndrome: A Case Report With Lamotrigine and a Review of the Literature.

INTRODUCTION: Restless Legs Syndrome (RLS) is a neurological disorder primarily treated with pregabalin and gabapentin, followed by dopamine agonists later in the process due to the risk of augmenting RLS symptoms. In addition, clinical reports have disclosed varying degrees of success employing other agents in patients unresponsive to traditional agents. Here, we present a patient who had success in the reduction of RLS symptoms with lamotrigine, a broad-spectrum anticonvulsant. Previously, lamotrigine had been used in 2 trials with successful treatment of RLS. CASE REPORT: We present a 58-year-old right-handed lady with long-standing history of smoking, hypertension, dyslipidaemia, prediabetes, gastro-esophageal reflux disease, asthma, strabismus, uterine cancer, severe and debilitating course of RLS accompanied by unexplained deterioration. The patient initially demonstrated abnormal sensation in all her limbs, which worsened with radiotherapy treatment, and was eventually diagnosed with RLS based on the diagnostic criteria. Subsequent examinations were unremarkable and revealed no further explanation for the deterioration of the RLS symptoms. While the complexity of the patient's medical history had exposed her to a variety of medications, she reported that only lamotrigine, in addition to her original regimen of methadone and pramipexole, offered significant symptomatic relief. It must be noted that no adverse side effects, including impulse-control disorder, were reported by the patient. CONCLUSIONS: We present a case of a woman whose deteriorating symptoms of RLS were successfully alleviated by the administration of lamotrigine. This is only the third case in the literature to have successfully utilized lamotrigine as a treatment option for RLS.

The 5-HT2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset.

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.

The mGluR2/3 orthosteric agonist LY-404,039 reduces dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.

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.

Effect of the mGlu4 positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset.

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.

5-HT1A agonists for levodopa-induced dyskinesia in Parkinson's disease.

Levodopa is the most effective agent for treating the symptoms of Parkinson's disease (PD). However, levodopa-induced dyskinesia remains a significant complication that manifests after few years of treatment, for which therapeutic options remain limited. Several agonists of the serotonin type 1A (5-HT1A) receptor with varying levels of efficacy and interaction at other sites, have been tested in the clinic. Clinical trials testing 5-HT1A agonists have yielded inconsistent results in alleviating dyskinesia, especially that the antidyskinetic benefit observed was often accompanied by an adverse effect on motor function. In this article, we summarize and analyze the various clinical trials performed with 5-HT1A agonists in PD patients with dyskinesia and offer perspectives on the future of this class of agents in PD.

After prolonged treatment with levodopa, patients with Parkinson's disease might start to experience abnormal involuntary movements, called 'dyskinesias'. These abnormal movements may be difficult to cope with since they can occur for several hours during the day and can hamper the quality of life. A potential approach to reduce the severity of dyskinesia, which has been the focus of extensive research, consists of stimulating a target inside the brain called the 5-HT_1A receptor. Several drugs harbouring this mechanism of action have been tested in clinical studies. Here, we provide an overview of these clinical studies and discuss their results.

Metabotropic glutamate receptors in Parkinson's disease.

Parkinson's disease (PD) is a complex disorder that leads to alterations in multiple neurotransmitter systems, notably glutamate. As such, several drugs acting at glutamatergic receptors have been assessed to alleviate the manifestation of PD and treatment-related complications, culminating with the approval of the N-methyl-d-aspartate (NMDA) antagonist amantadine for l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. Glutamate elicits its actions through several ionotropic and metabotropic (mGlu) receptors. There are 8 sub-types of mGlu receptors, with sub-types 4 (mGlu4) and 5 (mGlu5) modulators having been tested in the clinic for endpoints pertaining to PD, while sub-types 2 (mGlu2) and 3 (mGlu3) have been investigated in pre-clinical settings. In this book chapter, we provide an overview of mGlu receptors in PD, with a focus on mGlu5, mGlu4, mGlu2 and mGlu3 receptors. For each sub-type, we review, when applicable, their anatomical localization and possible mechanisms underlying their efficacy for specific disease manifestation or treatment-induced complications. We then summarize the findings of pre-clinical studies and clinical trials with pharmacological agents and discuss the potential strengths and limitations of each target. We conclude by offering some perspectives on the potential use of mGlu modulators in the treatment of PD.

Distribution of [11C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.

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.

Pharmacokinetic profile of bitopertin, a selective GlyT1 inhibitor, in the rat.

Bitopertin, a selective glycine transporter 1 (GlyT1) inhibitor, has been extensively studied for the treatment of schizophrenia, with known safety and tolerability profiles in the clinic. Whereas several rodent experiments have been reported, the pharmacokinetic (PK) profile of bitopertin in rodents has not been extensively reported, as only two studies disclosed limited PK parameters in male rats after oral administration. Here, we determined the PK profile of bitopertin in female Sprague-Dawley rats. Blood samples were taken serially, before and after sub-cutaneous (0.03, 0.1, 0.3, 1, and 3 mg/kg) or intra-venous (0.1 mg/kg) administration. Plasma levels were determined by high-performance liquid chromatography coupled with heat-assisted electrospray ionisation tandem mass spectrometry (HPLC-HESI MS/MS). Subsequently, PK parameters were calculated using non-compartmental analysis, including area under the curve (AUC), time (Tmax) to maximal plasma concentration (Cmax), clearance (CL), volume of distribution (Vz), as well as half-life (T1/2). Following sub-cutaneous injection, bitopertin exhibited dose-dependent AUC0-∞ (439.6-34,018.9 ng/mL) and Tmax (3.7-24.0 h), a very long terminal T1/2 (35.06-110.32 h) and low CL (0.07-0.13 L/h/kg), suggesting that bitopertin is slowly absorbed and eliminated in the rat. The observed relationship between dose and the extent of drug exposure (AUC) was linear. Following administration of all sub-cutaneous doses, measured bitopertin plasma levels were comparable to levels achieved with doses already administered in the clinic. We hope that our results will be useful in the design of pre-clinical experiments in which this drug will eventually be administered sub-cutaneously.

Anti-parkinsonian effect of the mGlu2 positive allosteric modulator LY-487,379 as monotherapy and adjunct to a low L-DOPA dose in the MPTP-lesioned marmoset.

In previous experiments, we have discovered that positive allosteric modulation of metabotropic glutamate 2 (mGlu2) receptors enhances the anti-parkinsonian action of an optimal dose of L-3,4-dihydroxyphenylalanine (L-DOPA). Whether selective mGlu2 positive allosteric modulation would also alleviate parkinsonian disability as monotherapy or as adjunct to a sub-optimal dose of L-DOPA has not been determined. Here, we assessed the anti-parkinsonian effect of mGlu2 positive allosteric modulation as monotherapy and adjunct to a sub-optimal dose of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets. The highly selective positive allosteric modulator (PAM) LY-487,379 was utilised to activate mGlu2 receptors. When administered as monotherapy, LY-487,379 10 mg/kg diminished global parkinsonism by 48% (P < 0.001) and increased duration of on-time by 7-fold, when compared to vehicle treatment (P < 0.05). When added to a sub-optimal dose of L-DOPA, LY-487,379 10 mg/kg decreased global parkinsonism by 44% (P < 0.001) and extended duration of on-time by 2.5-fold (P < 0.01). Our results indicate that selective mGlu2 positive allosteric modulation elicits anti-parkinsonian benefits as monotherapy and as adjunct to sub-optimal dose of L-DOPA paradigms, potentially suggesting that mGlu2 PAMs may have a therapeutic niche early in the treatment of PD as DOPA-sparing agents.

Effect of glycine transporter 1 inhibition with bitopertin on parkinsonism and L-DOPA induced dyskinesia in the 6-OHDA-lesioned rat.

Dyskinesia remains an unmet need in Parkinson's disease (PD). We have previously demonstrated that glycine transporter 1 (GlyT1) inhibition with ALX-5407 reduces dyskinesia and slightly improves parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine the effect of bitopertin, a clinically-tested GlyT1 inhibitor, on parkinsonism and dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. To do so, we assessed the effect of bitopertin on parkinsonism as monotherapy and as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA). We then assessed the efficacy of bitopertin on dyskinesia in the context of acute challenge and chronic administration studies. Lastly, we evaluated whether de novo treatment with bitopertin, started concurrently with L-DOPA, would diminish the development of dyskinesia. We discovered that bitopertin (0.3 mg/kg), when administered alone, reduced the severity of parkinsonism by 35% (P < 0.01). As adjunct to a low dose of L-DOPA, bitopertin (3 mg/kg) enhanced the anti-parkinsonian effect of L-DOPA by 36% (P < 0.05). Moreover, the acute addition of bitopertin (0.03 mg/kg) to L-DOPA reduced dyskinesia by 27% (P < 0.001), and there was no tolerance to the anti-dyskinetic benefit after 4 weeks of daily administration. Lastly, bitopertin (0.03 mg/kg) started concurrently with L-DOPA, also attenuated the development of dyskinesia, by 33% (P < 0.01), when compared to L-DOPA alone. Our results suggest that GlyT1 inhibition may simultaneously reduce parkinsonism and L-DOPA-induced dyskinesia and represents a novel approach to treat, possibly prevent, motor complications in PD.

Quantitative determination of LY-404,039, a metabotropic glutamate 2/3 receptor agonist, in rat plasma using chemical derivatization and HPLC-MRM/MS.

A rapid, selective and sensitive method was developed and validated for the determination of LY-404,039 concentration in rat plasma using a butylation derivatization step to improve chromatographic characteristics and enhance signal intensity. The method consisted of a protein precipitation extraction followed by derivatization with butanol/HCl and analysis by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The separation was achieved using a 100 × 2.1 mm (2.6 µm) Thermo Scientific Accucore RP-MS column combined with an isocratic mobile phase composed of 40:60 acetonitrile-0.1% formic acid in water. An analytical range of 2.0-1,000 ng/ml was validated and used to quantify LY-404,039 in rat plasma. The novel method met all of the requirements of specificity, sensitivity, linearity, precision, accuracy and stability. A pharmacokinetic study was performed in rats and the novel analytical method was used as a routine analysis method to provide enhanced measurements of plasma concentrations of LY-404,039. The plasma pharmacokinetic results indicate very short terminal half-life (0.27 h ± 0.8) and high clearance (0.97 L/h/kg ± 0.12), suggesting that LY-404,039 is rapidly eliminated in the rat. Dose-dependent pharmacokinetics were observed following subcutaneous administration of LY-404,039 at doses of 0.1, 0.3 and 1.0 mg/kg.

Evaluation of the effects of the mGlu2/3 antagonist LY341495 on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

BACKGROUND: We have previously demonstrated that the metabotropic glutamate 2 and 3 (mGlu2/3) antagonist LY341495 reverses the anti-dyskinetic and anti-psychotic benefits conferred by mGlu2 activation and serotonin 2A (5-HT2A) antagonism. Here, we hypothesised that a higher dose of LY341495, associated with a higher antagonistic effect at mGlu3 receptors, would result in a reduction of the reversal of mGlu2 activation and 5-HT2A blockade on dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. METHODS: After induction of parkinsonism with MPTP, marmosets entered 3 streams of experiments, in which the following treatments were administered, in combination with l-3,4-dihydroxyphenylalanine (L-DOPA), after which dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were rated: 1. vehicle/vehicle, LY354740 (mGlu2/3 orthosteric agonist)/vehicle, LY354740/LY341495 1 mg/kg and LY354740/LY341495 3 mg/kg; 2. vehicle/vehicle, LY487379 (mGlu2 positive allosteric modulator)/vehicle, LY487379/LY341495 1 mg/kg and LY487379/LY341495 3 mg/kg; 3. vehicle/vehicle, EMD-281,014 (5-HT2A antagonist)/vehicle, EMD-281,014/LY341495 1 mg/kg and EMD-281,014/LY341495 3 mg/kg. RESULTS: Each of LY354740, LY487379 and EMD-281,014 reduced the severity of L-DOPA-induced dyskinesia, by 55%, 39% and 40%, respectively (all p < 0.001), as well as the severity of PLBs, by 48%, 36% and 41%, respectively (all p < 0.001). Adding LY341495 1 and 3 mg/kg to each of LY354740, LY487379 and EMD-281,014 resulted in a dose-dependent reversal of their anti-dyskinetic and anti-psychotic actions. No effect on the anti-parkinsonian action of L-DOPA was noted with any treatment combination. CONCLUSION: These results suggest that an antagonistic effect at mGlu3 receptors may not be sufficient to overcome the deleterious effect of mGlu2 blockade on dyskinesia in PD. It remains to be seen whether similar effects would have been obtained with a selective mGlu3 antagonist.