Nitric Oxide Signaling in the Striatum

West, Anthony R.

doi:10.1016/b978-0-12-802206-1.00011-8

Cited by 3 publications

(4 citation statements)

References 201 publications

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“…A more detailed understanding of NO–cGMP signalling in specific MSNs and local interneurons may lead to novel treatments to restore motor function in hyperkinetic movement disorders (Frost Nylén et al, 2021). Striatal NO also modulates postsynaptic depression and the dopamine–glutamate interaction, both crucial for motor control (Calabresi et al, 1999; Rafalovich et al, 2015; West, 2016). Furthermore, dysregulation of corticostriatal transmission to MSNs is implicated in the pathogenesis of LIDs (Calabresi et al, 2014; Cenci et al, 2018; De Deurwaerdère et al, 2017; Espay et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Despite constituting less than 1% of the total striatal neuronal population (Rymar et al, 2004), nNOS‐containing interneurons greatly influence striatal neurotransmission due to their extensively ramified axons that project throughout the striatum (Kawaguchi, 1997). nNOS‐containing interneurons receive strong glutamatergic innervation from the cortex (Salin et al, 1990; Vuillet et al, 1989), as well as nigrostriatal dopamine innervation that acts on the D1/5 class of receptors (Centonze et al, 2003; Fujiyama & Masuko, 1996; West, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

Ribeiro,

Guimarães,

Bariotto‐dos‐Santos

et al. 2024

Eur J of Neuroscience

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Levodopa (L‐DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L‐DOPA‐induced dyskinesias (LIDs). Dysregulation of the nitric oxide–cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham‐operated and 6‐hydroxydopamine‐lesioned rats chronically treated with vehicle or L‐DOPA, respectively. In sham‐operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6‐hydroxydopamine‐lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L‐DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

Ribeiro,

Guimarães,

Bariotto‐dos‐Santos

et al. 2024

Eur J of Neuroscience

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“…D2 receptor antagonists increase cAMP in indirect pathway neurons by reducing the D2 receptor brake on cyclase activity. D1 receptor stimulation and D2 receptor inhibition also increase cGMP synthesis in striatum (West, 2016 ). Dopamine-regulated striatal cGMP synthesis is driven by nitric oxide (NO) stimulation of soluble guanylate cyclase, which is expressed by both direct and indirect pathway MSNs.…”

Section: Striatal Msns–a Key Cellular Target Of Antipsychotic Drugsmentioning

confidence: 99%

“…Similar effects on both basal and PDE10A inhibitor enhanced cGMP levels are observed after systemic administration of NOS or nNOS-selective inhibitors. Genetic deletion of nNOS or administration of nNOS inhibitors also completely block the increase in cGMP caused by D2 antagonists or dopamine D1 receptor agonists (West, 2016 ). The locus of nNOS driving this striatal cGMP synthesis is nNOS-positive striatal interneurons.…”

Section: Pde10a Regulation Of Cyclic Nucleotide Signaling In Msnsmentioning

confidence: 99%

PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

2021

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PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.

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Nitric Oxide–Soluble Guanylyl Cyclase–Cyclic GMP Signaling in the Striatum: New Targets for the Treatment of Parkinson's Disease?

West¹,

Tseng²

2011

Front. Syst. Neurosci.

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Striatal nitric oxide (NO)-producing interneurons play an important role in the regulation of corticostriatal synaptic transmission and motor behavior. Striatal NO synthesis is driven by concurrent activation of NMDA and dopamine (DA) D1 receptors. NO diffuses into the dendrites of medium-sized spiny neurons which contain high levels of NO receptors called soluble guanylyl cyclases (sGC). NO-mediated activation of sGC leads to the synthesis of the second messenger cGMP. In the intact striatum, transient elevations in intracellular cGMP primarily act to increase neuronal excitability and to facilitate glutamatergic corticostriatal transmission. NO–cGMP signaling also functionally opposes the inhibitory effects of DA D2 receptor activation on corticostriatal transmission. Not surprisingly, abnormal striatal NO–sGC–cGMP signaling becomes apparent following striatal DA depletion, an alteration thought to contribute to pathophysiological changes observed in basal ganglia circuits in Parkinson's disease (PD). Here, we discuss recent developments in the field which have shed light on the role of NO–sGC–cGMP signaling pathways in basal ganglia dysfunction and motor symptoms associated with PD and l-DOPA-induced dyskinesias.

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Nitric Oxide Signaling in the Striatum

Cited by 3 publications

References 201 publications

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

Nitric Oxide–Soluble Guanylyl Cyclase–Cyclic GMP Signaling in the Striatum: New Targets for the Treatment of Parkinson's Disease?

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