Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys

Morin, Nicolas; Morissette, Marc; Grégoire, Laurent; Paolo, Thérèse Di

doi:10.1016/j.pnpbp.2014.07.006

Cited by 10 publications

(3 citation statements)

References 87 publications

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“…The treatment-induced sprouting of 5-HT axon terminals requires a previous severe DA denervation of the affected region, as well as a partial lesion of 5-HT afferents, as it does not seem to occur when LID is produced in animal models of PD having intact serotonin projections [cf. ( 109 )].…”

Section: Debate On the Plasticity Of The Serotonin System In Lid And mentioning

confidence: 99%

Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications

2014

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The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson’s disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

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Section: Debate On the Plasticity Of The Serotonin System In Lid And mentioning

confidence: 99%

Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications

2014

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“…Indeed, altered dopaminergic and non-dopaminergic neurotransmission, including also serotonergic, adenosine, cannabinoid, opioid, GABAergic, adrenergic, histaminergic, and cholinergic systems are observed in LID ( 12 , 51 ). For example, serotoninergic dysfunctions in LID are well documented ( 114 , 115 ) and serotonin neurotransmission can interact with iGlu ( 116 – 118 ) and mGlu receptors ( 119 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Treatments Inhibiting Levodopa-Induced Dyskinesias in MPTP-Lesioned Monkeys: Brain Glutamate Biochemical Correlates

Morin

Paolo

2014

Front. Neurol.

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Anti-glutamatergic drugs can relieve Parkinson’s disease (PD) symptoms and decrease l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID). This review reports relevant studies investigating glutamate receptor subtypes in relation to motor complications in PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Antagonists of the ionotropic glutamate receptors, such as N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, display antidyskinetic activity in PD patients and animal models such as the MPTP monkey. Metabotropic glutamate 5 (mGlu5) receptor antagonists were shown to reduce the severity of LID in PD patients as well as in already dyskinetic non-human primates and to prevent the development of LID in de novo treatments in non-human primates. An increase in striatal post-synaptic NMDA, AMPA, and mGlu5 receptors is documented in PD patients and MPTP monkeys with LID. This increase can be prevented in MPTP monkeys with the addition of a specific glutamate receptor antagonist to the l-DOPA treatment and also with drugs of various pharmacological specificities suggesting multiple receptor interactions. This is yet to be well documented for presynaptic mGlu4 and mGlu2/3 and offers additional new promising avenues.

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“…However, excess glutamate can be excitotoxic to neurons. A number of studies show a strong correlation between abnormal glutamatergic signaling pathway and neurodegenerative/psychiatric diseases, including Alzheimer's disease (Takahashi et al, 2015 ; Haas et al, 2016 ), Parkinson's disease (Alvarsson et al, 2015 ; Morin et al, 2015 ), Huntington's disease (Behrens et al, 2002 ; Estrada-Sánchez et al, 2009 ), amyotrophic lateral sclerosis (Plaitakis et al, 1988 ; Veyrat-Durebex et al, 2015 ), epilepsy (Wong et al, 2015 ), ischemia (Dhami et al, 2013 ), migraine (Peres et al, 2004 ; Campos et al, 2013 ), schizophrenia (Spangaro et al, 2012 ; Matsuno et al, 2015 ), depression (Berman et al, 2000 ; Duric et al, 2013 ; Peng et al, 2016 ), addiction (Aitta-aho et al, 2012 ; Perry et al, 2016 ), and autism spectrum disorder (Bristot Silvestrin et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

The Influence of Na+, K+-ATPase on Glutamate Signaling in Neurodegenerative Diseases and Senescence

et al. 2016

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Decreased Na+, K+-ATPase (NKA) activity causes energy deficiency, which is commonly observed in neurodegenerative diseases. The NKA is constituted of three subunits: α, β, and γ, with four distinct isoforms of the catalytic α subunit (α1−4). Genetic mutations in the ATP1A2 gene and ATP1A3 gene, encoding the α2 and α3 subunit isoforms, respectively can cause distinct neurological disorders, concurrent to impaired NKA activity. Within the central nervous system (CNS), the α2 isoform is expressed mostly in glial cells and the α3 isoform is neuron-specific. Mutations in ATP1A2 gene can result in familial hemiplegic migraine (FHM2), while mutations in the ATP1A3 gene can cause Rapid-onset dystonia-Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC), as well as the cerebellar ataxia, areflexia, pescavus, optic atrophy and sensorineural hearing loss (CAPOS) syndrome. Data indicates that the central glutamatergic system is affected by mutations in the α2 isoform, however further investigations are required to establish a connection to mutations in the α3 isoform, especially given the diagnostic confusion and overlap with glutamate transporter disease. The age-related decline in brain α2∕3 activity may arise from changes in the cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG) pathway. Glutamate, through nitric oxide synthase (NOS), cGMP and PKG, stimulates brain α2∕3 activity, with the glutamatergic N-methyl-D-aspartate (NMDA) receptor cascade able to drive an adaptive, neuroprotective response to inflammatory and challenging stimuli, including amyloid-β. Here we review the NKA, both as an ion pump as well as a receptor that interacts with NMDA, including the role of NKA subunits mutations. Failure of the NKA-associated adaptive response mechanisms may render neurons more susceptible to degeneration over the course of aging.

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Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys

Cited by 10 publications

References 87 publications

Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications

Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications

Pharmacological Treatments Inhibiting Levodopa-Induced Dyskinesias in MPTP-Lesioned Monkeys: Brain Glutamate Biochemical Correlates

The Influence of Na+, K+-ATPase on Glutamate Signaling in Neurodegenerative Diseases and Senescence

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