Role for the nicotinic cholinergic system in movement disorders; therapeutic implications

Abstract

A large body of evidence using experimental animal models shows that the nicotinic cholinergic system is involved in the control of movement under physiological conditions. This work raised the question whether dysregulation of this system may contribute to motor dysfunction and whether drugs targeting nicotinic acetylcholine receptors (nAChRs) may be of therapeutic benefit in movement disorders. Accumulating preclinical studies now show that drugs acting at nAChRs improve drug-induced dyskinesias. The general nAChR agonist nicotine, as well as several nAChR agonists (varenicline, ABT-089 and ABT-894) reduce L-dopa-induced abnormal involuntary movements or dyskinesias up to 60% in parkinsonian nonhuman primates and rodents. These dyskinesias are potentially debilitating abnormal involuntary movements that arise as a complication of L-dopa therapy for Parkinson’s disease. In addition, nicotine and varenicline decrease antipsychotic-induced abnormal involuntary movements in rodent models of tardive dyskinesia. Antipsychotic-induced dyskinesias frequently arise as a side effect of chronic drug treatment for schizophrenia, psychosis and other psychiatric disorders. Preclinical and clinical studies also show that the nAChR agonist varenicline improves balance and coordination in various ataxias. Lastly, nicotine has been reported to attenuate the dyskinetic symptoms of Tourette’s disorder. Several nAChR subtypes appear to be involved in these beneficial effects of nicotine and nAChR drugs including α4β2*, α6β2* and α7 nAChRs (the asterisk indicates the possible presence of other subunits in the receptor). Overall, the above findings, coupled with nicotine’s neuroprotective effects, suggest that nAChR drugs have potential for future drug development for movement disorders.

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

“…This lack of effect on motor deficits is in agreement with previous work showing that cholinergic interneuron activation/ablation, nAChR agonists/antagonist treatment and mAChR antagonist treatment did not modulate lesion-induced motor impairment (Ding et al, 2011; Maurice et al, 2015; Quik et al, 2008; Quik et al, 2014). These data directly show that striatal cholinergic interneuron activation selectively regulates LIDs with no effect on motor impairment.…”

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats

“…Results showed increased cleaved caspase-3 and reduced BDNF levels, which suggest that the neuronal and astroglial losses provoked by GAL injection are at least in part due to apoptosis pathway. Impairment in the cerebellar cholinergic system has been implicated in several motor diseases, due the involvement of the cholinergic system in movement control [67]. Acetylcholine plays a key role in cell survival, and it has been associated with neurodegenerative diseases [34,36].…”

Duality of Antidepressants and Neuroprotectants

“…Thus, in Parkinson’s disease cell models, nicotine protects against endogenous substances such as salsolinol and aminochrome that selectively damage dopaminergic cells (Copeland et al 2005, 2007; Das and Tizabi 2009; Ramlochansingh et al 2011; Munoz et al 2012). Similarly in animal studies, including non-human primates, it has been shown that nicotine delays Parkinson’s disease-like symptoms induced by MPTP (Quik et al 2006, 2009, 2014). Moreover, nicotine may also reduce l -Dopa-induced dyskinesia (Quik et al 2014).…”

“…Similarly in animal studies, including non-human primates, it has been shown that nicotine delays Parkinson’s disease-like symptoms induced by MPTP (Quik et al 2006, 2009, 2014). Moreover, nicotine may also reduce l -Dopa-induced dyskinesia (Quik et al 2014). A mechanism of nicotine protection against Parkinson’s disease may involve inhibition of astrocyte activation and inflammatory suppression (Liu et al 2012).…”