Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders

Quik, Maryka; Boyd, James T.; Bordia, Tanuja; Perez, Xiomara A.

doi:10.1093/ntr/nty063

Cited by 29 publications

(41 citation statements)

References 209 publications

(264 reference statements)

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“…GABA-ergic projection neurons, MSNs, express nicotinic receptors only to a very limited extent (Bordia and Perez, 2019; Loonen et al, 2019). The influence of nAChRs on neurotransmitter release from glutamatergic and dopaminergic terminals suggests a possible role in the pathogenesis and treatment of certain movement disorders (particularly levodopa-induced dyskinesia); this is supported by available evidence (Quik et al 2019). The effects of drugs antagonising muscarinic receptors, however, largely surpass those of substances which affect nAChRs and are therefore considered in this article in more detail.…”

Section: Cholinergic Receptorsmentioning

confidence: 82%

Neurobiological mechanisms associated with antipsychotic drug-induced dystonia

Loonen

Иванова

2020

J Psychopharmacol

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Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.

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Section: Cholinergic Receptorsmentioning

confidence: 82%

Neurobiological mechanisms associated with antipsychotic drug-induced dystonia

Loonen

Иванова

2020

J Psychopharmacol

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“…[58,59]. There is also emerging research that suggest that nicotine and other drugs that act as nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson’s disease, Alzheimer’s, and related neurological disorders, making the large-scale production of highly purified nicotine at low costs for therapeutics necessary [60,61].…”

Section: Introductionmentioning

confidence: 99%

Increased Leaf Nicotine Content by Targeting Transcription Factor Gene Expression in Commercial Flue-Cured Tobacco (Nicotiana tabacum L.)

Liu

Kotova

Timko

2019

Genes

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Nicotine, the most abundant pyridine alkaloid in cultivated tobacco (Nicotiana tabacum L.), is a potent inhibitor of insect and animal herbivory and a neurostimulator of human brain function. Nicotine biosynthesis is controlled developmentally and can be induced by abiotic and biotic stressors via a jasmonic acid (JA)-mediated signal transduction mechanism involving members of the APETALA 2/ethylene-responsive factor (AP2/ERF) and basic helix-loop-helix (bHLH) transcription factor (TF) families. AP2/ERF and bHLH TFs work combinatorically to control nicotine biosynthesis and its subsequent accumulation in tobacco leaves. Here, we demonstrate that overexpression of the tobacco NtERF32, NtERF221/ORC1, and NtMYC2a TFs leads to significant increases in nicotine accumulation in T2 transgenic K326 tobacco plants before topping. Up to 9-fold higher nicotine production was achieved in transgenics overexpressing NtERF221/ORC1 under the control of a constitutive GmUBI3 gene promoter compared to wild-type plants. The constitutive 2XCaMV35S promoter and a novel JA-inducible 4XGAG promoter were less effective in driving high-level nicotine formation. Methyljasmonic acid (MeJA) treatment further elevated nicotine production in all transgenic lines. Our results show that targeted manipulation of NtERF221/ORC1 is an effective strategy for elevating leaf nicotine levels in commercial tobacco for use in the preparation of reduced risk tobacco products for smoking replacement therapeutics.

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“…With elaboration of complex neurotransmitter interactions in the basal ganglia and novel agents becoming available to target specific receptor subtypes, future trials may yet confirm selective muscarinic or nicotinic agents that could reduce TD movements [ 105 , 110 - 112 ]. Given the dense localization of muscarinic receptors (mAChRs) in the striatum, they may constitute a viable target affecting TD [ 110 , 113 ].…”

Section: Pharmacotherapy Of Tardive Dyskinesiamentioning

confidence: 99%

“…The role of diminished nicotinic receptor (nAChR) function underlying TD is suggested by the fact that D2-receptor blockade may result in reduced binding and loss of nAChRs [ 105 ]. Since activation of nAChR normally evokes release of striatal dopamine, nicotinic agonists should acutely worsen TD, but long-term administration leading to nAChR desensitization may reduce dopamine release and potentially suppress dyskinesias [ 111 , 114 ]. In fact, chronic administration of nicotine does indeed attenuate haloperidol-induced vacuous chewing movements in rodent and primate models [ 115 , 116 ].…”

Section: Pharmacotherapy Of Tardive Dyskinesiamentioning

confidence: 99%

Recent Advances in the Pharmacology of Tardive Dyskinesia

Caroff

2020

Clin Psychopharmacol Neurosci

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Tardive dyskinesia (TD) is a syndrome of abnormal involuntary movements that follows treatment with dopamine D2-receptor antagonists. Recent approval of vesicular monoamine transporter-2 (VMAT2) inhibitors offers hope for reducing the impact of TD. Although these drugs represent a significant advance in patient care and a practical step forward in providing relief for patients with TD, understanding of the pharmacology of TD that could inform future research to prevent and reverse TD remains incomplete. This review surveys evidence for the effectiveness of VMAT2 inhibitors and other agents in the context of theories of pathogenesis of TD. In patients for whom VMAT2 inhibitors are ineffective or intolerable, as well as for extending therapeutic options and insights regarding underlying mechanisms, a review of clinical trial results examined as experimental tests of etiologic hypotheses is worthwhile. There are still compelling reasons for further investigations of the pharmacology of TD, which could generate alternative preventive and potentially curative treatments. Finally, benefits from novel drugs are best realized within an overall treatment strategy addressing the condition and needs of individual patients.

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Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders

Cited by 29 publications

References 209 publications

Neurobiological mechanisms associated with antipsychotic drug-induced dystonia

Neurobiological mechanisms associated with antipsychotic drug-induced dystonia

Increased Leaf Nicotine Content by Targeting Transcription Factor Gene Expression in Commercial Flue-Cured Tobacco (Nicotiana tabacum L.)

Recent Advances in the Pharmacology of Tardive Dyskinesia

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