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Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders.

ABSTRACT: Emerging studies indicate that striatal cholinergic interneurons play an important role in synaptic plasticity and motor control under normal physiological conditions, while their disruption may lead to movement disorders. Here we discuss the involvement of the cholinergic system in motor dysfunction, with a focus on the role of the nicotinic cholinergic system in Parkinson's disease and drug-induced dyskinesias. Evidence for a role for the striatal nicotinic cholinergic system stems from studies showing that administration of nicotine or nicotinic receptor drugs protects against nigrostriatal degeneration and decreases L-dopa-induced dyskinesias. In addition, nicotinic receptor drugs may ameliorate tardive dyskinesia, Tourette's syndrome and ataxia, although further study is required to understand their full potential in the treatment of these disorders. A role for the striatal muscarinic cholinergic system in movement disorders stems from studies showing that muscarinic receptor drugs acutely improve Parkinson's disease motor symptoms, and may reduce dyskinesias and dystonia. Selective stimulation or lesioning of striatal cholinergic interneurons suggests they are primary players in this regulation, although multiple central nervous systems appear to be involved. IMPLICATIONS:Accumulating data from preclinical studies and clinical trials suggest that drugs targeting CNS cholinergic systems may be useful for symptomatic treatment of movement disorders. Nicotinic cholinergic drugs, including nicotine and selective nAChR receptor agonists, reduce L-dopa-induced dyskinesias, as well as antipsychotic-induced tardive dyskinesia, and may be useful in Tourette's syndrome and ataxia. Subtype selective muscarinic cholinergic drugs may also provide effective therapies for Parkinson's disease, dyskinesias and dystonia. Continued studies/trials will help address this important issue.

SUBMITTER: Quik M

PROVIDER: S-EPMC6379038 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders.

Quik Maryka M Boyd James T JT Bordia Tanuja T Perez Xiomara X

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 20190201 3

Emerging studies indicate that striatal cholinergic interneurons play an important role in synaptic plasticity and motor control under normal physiological conditions, while their disruption may lead to movement disorders. Here we discuss the involvement of the cholinergic system in motor dysfunction, with a focus on the role of the nicotinic cholinergic system in Parkinson's disease and drug-induced dyskinesias. Evidence for a role for the striatal nicotinic cholinergic system stems from studie ...[more]

PMID: 30137517

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Project description:G protein coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of ?-arrestin functionality. ?-Arrestins were first thought to only regulate receptor desensitization and internalization - exemplified by the action of visual arrestin with respect to rhodopsin desensitization. Nearly 20 years ago, it was found that rather than controlling GPCR signal termination, productive ?-arrestin dependent GPCR signaling paradigms were highly dependent on multi-protein complex formation and generated long-lasting cellular effects, in contrast to G protein signaling which is transient and functions through soluble second messenger systems. ?-Arrestin signaling was then first shown to activate mitogen activated protein kinase signaling in a G protein-independent manner and eventually initiate protein transcription - thus controlling expression patterns of downstream proteins. While the possibility of developing ?-arrestin biased or functionally selective ligands is now being investigated, no additional research has been performed on its possible contextual specificity in treating age-related disorders. The ability of ?-arrestin-dependent signaling to control complex and multidimensional protein expression patterns makes this therapeutic strategy feasible, as treating complex age-related disorders will likely require therapeutics that can exert network-level efficacy profiles. It is our understanding that therapeutically targeting G protein-independent effectors such as ?-arrestin will aid in the development of precision medicines with tailored efficacy profiles for disease/age-specific contextualities.

Dataset Information

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders.

Publications

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders.

Similar Datasets

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